Mercaptoalkanoylamino and acylmercaptoalkanoylamino benzoxazepines and benzothiazepines

ABSTRACT

Compounds of the formula ##STR1## wherein X 1  is ##STR2## are disclosed. These compounds possess inhibitory activity against angiotensin converting enzyme and neutral endopeptidase and thus useful as cardiovascular agents.

PRIOR APPLICATIONS

This application is a division of Ser. No. 676,769 filed Jul. 8, 1996,now U.S. Pat. No. 5,723,457 which is a division of Ser. No. 160,540filed Dec. 1, 1993, now U.S. Pat. No. 5,552,397, which is acontinuation-in-part of Ser. No. 061,606 filed May 13, 1993, nowabandoned, which is a continuation-in-part of Ser. No. 884,664 filed May18, 1992, now abandoned.

BACKGROUND OF THE INVENTION

Captopril, (S)-1-(3-mercapto-2-methyl-1-oxopropyl)-L-proline, having thestructural formula ##STR3## is an orally active angiotensin convertingenzyme inhibitor useful for treating hypertension and congestive heartfailure. See Ondetti et al. U.S. Pat. No. 4,105,776.

Enalapril, (S)-1- N-1-(ethoxycarbonyl)-3-phenypropyl!-L-alanyl!-L-proline, having thestructural formula ##STR4## is also an orally active angiotensinconverting enzyme inhibitor. Enalapril contains the L-alanyl-L-prolinedipeptide. A related compound, lisinopril, also possesses oralangiotensin converting enzyme inhibitor activity and contains theL-lysyl-L-proline dipeptide. See Harris et al. U.S. Pat. No. 4,374,829.

Haslanger et al. in U.S. Pat. No. 4,749,688 disclose treatinghypertension by administering neutral metalloendopeptidase inhibitorsalone or in combination with atrial peptides or angiotensin convertingenzyme inhibitors.

Neustadt in U.S. Pat. No. 5,075,302 disclose that mercaptoacylaminolactams of the formula ##STR5## wherein Y includes propylene andbutylene, R¹ is lower alkyl, aryl or heteroaryl, and R² is hydrogen,lower alkyl, lower alkoxy lower alkyl, aryl-lower alkyl orheteroaryl-lower alkyl are endopeptidase inhibitors. Neustadt discloseemploying such compounds alone or in combination with angiotensinconverting enzyme inhibitors to treat cardiovascular diseases such ashypertension, congestive heart failure, edema, and renal insufficiency.

Delaney et al. U.K. Patent 2,207,351 disclose that endopeptidaseinhibitors produce diuresis and natriuresis and are useful alone or incombination with angiotensin converting enzyme inhibitors for thereduction of blood pressure. Delaney et al. include various mercapto andacylmercapto amino acids and dipeptides among their endopeptidaseinhibiting compounds.

Flynn et al. in European Patent Application 481,522 disclose dualinhibitors of enkephalinase and angiotensin converting enzyme of theformulas ##STR6## wherein n is zero or one and Z is O, S, -NR₆ - or##STR7## Additional tricyclic dual inhibitors are disclosed bywarshawsky et al. in European Patent Applications 534,363, 534,396 and534,492.

SUMMARY OF THE INVENTION

This invention is directed to novel compounds possessing bothangiotensin converting enzyme inhibitory activity and neutralendopeptidase inhibitory activity and methods of preparing suchcompounds. This invention is also directed to pharmaceuticalcompositions containing such dual inhibiting compounds orpharmaceutically acceptable salts thereof and the method of using suchcompositions. The dual inhibitory compounds of this invention are thoseof the formula (I) ##STR8## and pharmaceutically acceptable saltsthereof wherein:

R₁ is hydrogen, ##STR9## or R₁₈ -S-; R₂ and R₁₉ are independentlyselected from hydrogen, alkyl, cycloalkyl--(CH₂)_(m) --, substitutedalkyl, aryl--(CH₂)_(m) --, substituted aryl--(CH₂)_(m) --, andheteroaryl--(CH₂)_(m) -- or R₂ and R₁₉ taken together with the carbonatom to which they are attached complete a cycloalkyl ring or abenzofused cycloalkyl ring;

n is zero or one;

m is zero or an integer from 1 to 6;

R₃ is alkyl, substituted alkyl, cycloalkyl--(CH₂)_(m) --,aryl--(CH₂)_(m) --, substituted aryl--(CH₂)_(m) --, orheteroaryl--(CH₂)_(m) --;

R₁₈ is alkyl, substituted alkyl, cycloalkyl--(CH₂)_(m) --,aryl--(CH₂)_(m) --, substituted aryl--(CH₂)_(m) --,heteroaryl--(CH₂)_(m) -- or --S--R₁₈ completes a symmetrical disulfidewherein R₁₈ is of the formula (II) ##STR10## X₁ is of the formula (III)##STR11## (IV) ##STR12## (V) ##STR13## (VI) ##STR14## (VII) ##STR15##(VIII) ##STR16## (IX) ##STR17## (X) ##STR18## (XI) ##STR19## (XII)##STR20## (XIII) ##STR21## R₄ and R₅ are independently selected fromhydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,cycloalkyl --(CH₂)_(m) --, aryl --(CH₂)_(m) --, substituted aryl--(CH₂)_(m) --, and heteroaryl --(CH₂)_(m) --, or one of R₄ and R₅ ishydroxy and the other is hydrogen, or R₄ and R₅ taken together with thecarbon to which they are attached complete a saturated cycloalkyl ringof 3 to 7 carbons, or R₄ and R₅ taken together with the carbon to whichthey are attached complete a keto substituent, i.e., ##STR22## R₆, R₈and R₁₀ are independently selected from hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, cycloalkyl --(CH₂)_(m) --,aryl--(CH₂)_(m) --, substituted aryl--(CH₂)_(m) --, andheteroaryl--(CH₂)_(m) --;

R₇, R₉ and R₁₁ are independently selected from hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl --(CH₂)_(m)--, aryl--(CH₂)_(m), substituted aryl --(CH₂)_(m) --, andheteroaryl--(CH₂)_(m) --, or R₆ and R₇ taken together with the carbon towhich they are attached complete a saturated cycloalkyl ring of 3 to 7carbons or R₈ and R₉ taken together with the carbon to which they areattached complete a saturated cycloalkyl ring of 3 to 7 carbons;

b is zero or one;

q is an integer from 1 to 4;

r is one or two;

s is zero, one or two;

t is one, two, or three;

v is one or two;

w is one or two; ##STR23## Y₄ is --CH₂ --, --(CH₂)₂ --, --(CH₂)₃ --,--O--, or --CH₂ --O--;

Z is O or two hydrogens;

R₁₂ is hydrogen, alkyl, substituted alkyl, aryl--(CH₂)_(m) --,substituted aryl--(CH₂)_(m) --, ##STR24## heteroaryl--(CH₂)_(m) --,##STR25## R₁₃ is hydrogen, lower alkyl, or substituted lower alkyl; R₁₄is hydrogen, lower alkyl, cycloalkyl, or phenyl;

R₁₅ is hydrogen, lower alkyl, lower alkoxy or phenyl;

R₁₆ is lower alkyl or aryl--(CH₂)_(m) --; and

R₁₇ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,cycloalkyl--(CH₂)_(m) --, aryl--(CH₂)_(m) --, substitutedaryl--(CH₂)_(m) --, or heteroaryl--(CH₂)_(m) --.

DETAILED DESCRIPTION OF THE INVENTION

The term "alkyl" refers to straight or branched chain radicals having upto seven carbon atoms. The term "lower alkyl" refers to straight orbranched radicals having up to four carbon atoms and is a preferredsubgrouping for the term alkyl.

The term "substituted alkyl" refers to such straight or branched chainradicals of 1 to 7 carbons wherein one or more, preferably one, two, orthree, hydrogens have been replaced by a hydroxy, amino, halo,trifluoromethyl, cyano, --NH(lower alkyl), --N(lower alkyl)₂, loweralkoxy, lower alkylthio or carboxy.

The term "substituted lower alkyl" refers to such straight or branchedchain radicals of 1 to 4 carbons wherein one hydrogen has been replacedby a hydroxy, amino, halo, trifluoromethyl, cyano, --NH(lower alkyl),--N(lower alkyl)₂, lower alkoxy, lower alkylthio, or carboxy.

The term "alkenyl" refers to straight or branched chain radicals of 3 to7 carbon atoms having one or two double bonds. Preferred "alkenyl"groups are straight chain radicals of 3 to 5 carbons having one doublebond.

The term "substituted alkenyl" refers to such straight or branchedradicals of 3 to 7 carbons having one or two double bonds wherein ahydrogen has been replaced by a hydroxy, amino, halo, trifluoromethyl,cyano, --NH(lower alkyl), --N(lower alkyl)₂, lower alkoxy, loweralkylthio, or carboxy.

The terms "lower alkoxy" and "lower alkylthio" refer to such lower alkylgroups as defined above attached to an oxygen or sulfur.

The term "cycloalkyl" refers to saturated rings of 3 to 7 carbon atoms.

The term "halo" refers to chloro, bromo, fluoro, and iodo.

The term "aryl" refers to phenyl, 1-naphthyl, and 2-naphthyl. The term"substituted aryl" refers to phenyl, 1-naphthyl, and 2-naphthyl having asubstituent selected from lower alkyl, lower alkoxy, lower alkylthio,halo, hydroxy, trifluoromethyl, amino, --NH(lower alkyl), or --N(loweralkyl)₂, di- and tri-substituted phenyl, 1-naphthyl, or 2-naphthylwherein said substituents are selected from methyl, methoxy, methylthio,halo, hydroxy, and amino.

The term "heteroaryl" refers to unsaturated rings of 5 or 6 atomscontaining one or two O and S atoms and/or one to four N atoms providedthat the total number of hetero atoms in the ring is 4 or less. Theheteroaryl ring is attached by way of an available carbon or nitrogenatom. Preferred heteroaryl groups include 2-, 3-, or 4-pyridyl,4-imidazolyl, 4-thiazolyl, 2- and 3-thienyl, and 2- and 3-furyl. Theterm heteroaryl also includes bicyclic rings wherein the five or sixmembered ring containing O, S, and N atoms as defined above is fused toa benzene or pyridyl ring. Preferred bicyclic rings are 2- and 3-indolyland 4- and 5-quinolinyl. The mono or bicyclic heteroaryl ring can alsobe additionally substituted at an available carbon atom by a loweralkyl, halo, hydroxy, benzyl, or cyclohexylmethyl. Also, if the mono orbicyclic ring has an available N-atom such N atom can also besubstituted by an N-protecting group such as ##STR26##2,4-dinitrophenyl, lower alkyl, benzyl, or benzhydryl.

The compounds of this invention wherein R₁ is hydrogen or ##STR27## andR₁₉ is hydrogen can be prepared by coupling the acylmercapto containingsidechain of the formula (XIV) ##STR28## with the intermediate of theformula (XV)

    H--X.sub.1

to give the product of the formula (XVI) ##STR29## wherein R₁₂ in thedefinition of X₁ is preferably an easily removable ester protectinggroup such as methyl, ethyl, t-butyl or benzyl. The above reaction canbe performed in an organic solvent such as dimethyl-formamide and in thepresence of a coupling reagent such asbenzotriazol-1-yloxytris-(dimethyl-amino)phosphoniumhexafluorophosphate, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,dicyclohexyl-carbodiimide, or carbonyldiimidazole. Alternatively, theacylmercapto carboxylic acid of formula XIV can be converted to anactivated form prior to coupling such as an acid chloride, mixedanhydride, symmetrical anhydride, activated ester, etc.

The product of formula XVI can be converted to the mercaptan product offormula I wherein R₁ is hydrogen and R₁₂ is hydrogen by methods known inthe art. For example when R₃ is methyl and R₁₂ is methyl or ethyltreatment with methanolic sodium hydroxide yields the product wherein R₁and R₁₂ are hydrogen and when R₃ is methyl and R₁₂ is t-butyl treatmentwith trifluoroacetic acid followed by ammonia yields the product whereinR₁ and R₁₂ are hydrogen.

The compounds of this invention wherein both R₂ and R₁₉ are other thanhydrogen and n is zero can be prepared by coupling the substitutedmercapto containing sidechain of the formula (XVII) ##STR30## with theintermediate of formula XV as described above to give the compound ofthe formula (XVIII) ##STR31## Treatment of the compound of formula XVIIIwith strong acid such as trifluoromethanesulfonic acid removes themethoxybenzyl protecting group and gives the corresponding product offormula I wherein R₁ is hydrogen.

The substituted mercapto containing compounds of formula XVII can beprepared by reacting the disubstituted carboxylic acid of the formula(XIX) ##STR32## with bis (4-methoxy)phenyl!methyl!disulfide in thepresence of lithium diisopropylamide.

The compounds of this invention wherein both R₂ and R₁₉ are other thanhydrogen and n is one can be prepared by coupling the acylmercaptocontaining sidechain of the formula (XX) ##STR33## with the intermediateof formula XV as described above to give the product of the formula(XXI) ##STR34##

The acylmercapto sidechain compound of formula XX can be prepared byreacting the substituted carboxylic acid of the formula (XXII) ##STR35##with para-toluenesulfonyl chloride in pyridine to give the lactone ofthe formula (XXIII) ##STR36## Treatment of the lactone of formula XXIIIwith a cesium thioacid of the formula (XXIV) ##STR37## in the presenceof dimethylformamide yields the desired acylmercapto sidechain offormula XX.

The products of formula I wherein X₁ contains a sulfoxide or sulfone canbe prepared by employing the intermediate of XV as the mercaptan, i.e.,s is zero, during the coupling reaction. The resulting product offormula XVI, XVIII, or XXI is then oxidized with a known oxidizingreagent such as metachloroperbenzoic acid, peracetic acid, ormonoperoxyphthalic acid, magnesium salt hexahydrate, etc. By controllingthe amount of oxidizing reagent and the time of the reaction, theproducts are obtained wherein s is one or two.

The products of formula I wherein R₁ is hydrogen can be acylated with anacyl halide of the formula (XXV) ##STR38## wherein halo is Cl or Br oracylated with an anhydride of the formula (XXVI) ##STR39## to give otherproducts of formula I wherein R₁ is ##STR40##

The products of formula I wherein R₁ is --S--R₁₈ and R₁₈ is alkyl,substituted alkyl, cycloalkyl--(CH₂)_(m) --, aryl--(CH₂)_(m) --,substituted aryl--(CH₂)_(m) -- or heteroaryl--(CH₂)_(m) -- can beprepared by reacting the products of formula I wherein R₁ is hydrogenwith a sulfonyl compound of the formula (XXVII)

    H.sub.3 C --SO.sub.2 --S--R.sub.18

in an aqueous alcohol solvent to yield the desired products. Thecompounds of formula XXVII are known in the literature or can beprepared by known methods, see for example, Smith et al., Biochemistry,14, p. 766-771 (1975).

The symmetrical disulfide products of formula I can be prepared bydirect oxidation of the product of formula I wherein R₁ is hydrogen withiodine as note, for example, Ondetti et al. U.S. Pat. No. 4,105,776.

The ester products of formula I wherein R₁₂ is ##STR41## can be preparedby treating the product of formula I wherein R₁₂ is hydrogen with acompound of the formula (XXVIII) ##STR42## wherein L is a leaving groupsuch as chloro, bromo, or tolylsulfonyloxy.

The acylmercaptoalkanoic acids of formula XIV are described in theliterature. See, for example, Ondetti et al. U.S. Pat. Nos. 4,105,776and 4,339,600, Haslanger et al. U.S. Pat. No. 4,801,609, etc.

The intermediates of formula XV are also described in the literature orare obtained by modifications of known procedures. For example, theintermediates of formula XV wherein X₁ is as defined in formula III aredisclosed by Thorsett et al., J. Med. Chem., 29, p. 251-260 (1988),Harris et al. in U.S. Pat. Nos. 4,587,050, 4,587,238, 4,629,787 andYanagisawa et al. in U.S. Pat. No. 4,734,410. The intermediates offormula XV wherein X₁ is as defined in formula IV are disclosed byYanagisawa et al., J., Med. Chem., 30, p. 1984-1991 (1987) and 31, p.422-428 (1988), Karanewsky in U.S. Pat. No. 4,460,579, Cheung et al. inU.S. Pat. No. 4,594,341, and Yanagisawa et al. in U.S. Pat. No.4,699,905. The intermediates of formula XV wherein X₁ is as defined informula V are disclosed by Karanewsky in U.S. Pat. Nos. 4,460,579 and4,711,884. The intermediates of formula XV wherein X₁ is as defined informula VI and Y₁ is --CH₂ --, --(CH₂)₂ -- of --(CH₂)₃ -- are disclosedby Watthey et al., J. Med. Chem., 28, p. 1511-1516 (1985) and Watthey inU.S. Pat. Nos. 4,410,520, 4,470,988, 4,473,575, 4,537,885 and 4,575,503and also by Parsons et al., Biochemical & Biophysical Research Comm.,117, p. 108-113 (1983) and in U.S. Pat. No. 4,873,235. The intermediatesof formula XV wherein X₁ is as defined in formula VI and Y₁ is S or Oare disclosed by Slade et al., J. Med. Chem., 28, p. 1517-1521 (1985)and in U.S. Pat. No. 4,477,464 and Itoh et al., Chem. Pharm. Bull., 34,p. 1128-1147 (1986) and 34, p. 2078-2089 (1986) as well as Sugihara etal. in U.S. Pat. No. 4,548,932 (Y is O) and Katakami et al. in U.S. Pat.No. 4,539,150 (Y is S). The intermediates of formula XV wherein X is asdefined in formula VII can be prepared by reduction of the correspondingintermediates wherein X₁ is as defined in formula VI. The intermediatesof formula XV wherein X₁ is as defined in formula VIII are disclosed byFlynn et al. in U.S. Pat. No. 4,973,585. The intermediates of formula XVwherein X is as defined in formula IX and Y₂ is S, --SO, or --SO₂ aredisclosed by Harris et al. and Patchett et al. in U.S. Pat. Nos.4,415,496 and 4,617,301. The intermediates for formula XV wherein X₁ isas defined in formula IX and Y₂ is CH₂ is disclosed by Thorsett, Actual.Chim. Ther., 13, p. 257-268 (1986). The intermediates of formula XVwherein X₁ is as defined in formula XI are disclosed by Attwood et al.,Federation of European Biochemical Studies, 165, p. 201-206 (1984) andin U.S. Pat. No. 4,512,994 and Natoff et al., Drugs Of The Future, 12,p. 475-483 (1987). The intermediates of formula XV wherein X₁ is asdefined in formula XII are disclosed by Huang et al. in U.S. Pat. No.4,465,679. The intermediates of formula XV wherein X₁ is as defined informula XIII are disclosed by Bolos et al. in Tetrahedron, 48, p.9567-9576 (1992).

The intermediates of formula XV wherein X₁ is as defined in formula IIIand q is one or two and R₇ is hydrogen can be prepared according to thefollowing process which is also part of this invention.

The N-phthalimido α-amino acid of the formula (XXIX) ##STR43## and theamino acid ester of the formula (XXX) ##STR44## wherein R₁₂ is an easilyremovable ester protecting group such as methyl, ethyl, or benzyl arecoupled to give the peptidyl compound of the formula (XXXI) ##STR45##This coupling reaction is preferably carried out in the presence of acoupling reagent such asbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphateor ethyl-3-(3-dimethylamino)propyl carbodiimide.

The compound of formula XXXI is oxidized such as by treatment withoxalyl chloride and dimethylsulfoxide or tetra-n-propyl ammoniumperruthenate and N-methylmorpholine N-oxide to give the compound of theformula (XXXII) ##STR46##

The compound of formula XXXII is cyclized by treatment with anon-aqueous acid such as trifluoroacetic acid, trifluoromethanesulfonic,hydrochloric acid, etc., to give the compound of the formula (XXXIII)##STR47##

The intermediate of formula XV wherein X₁ is as defined in formula IIIand q is one or two and R₆ and R₇ are both hydrogen can be prepared bytreating the compound of formula XXXIII with a silyl hydride such astriethylsilane, diphenylmethylsilane, phenylmethylsilane, etc., and aLewis acid catalyst such as stannic chloride, titanium tetrachloride,stannic bromide, boron trifluoride etherate, etc., followed byesterification of the carboxyl group and subsequent treatment withhydrazine hydrate to remove the N-phthaloyl protecting group.

The intermediate of formula XV wherein X₁ is as defined in formula IIIand q is one or two, R₇ is hydrogen, and R₆ is other than hydrogen canbe prepared from the compound of formula XXXIII. For example, when R₆ isalkenyl or substituted alkenyl of 3 to 7 carbons, treatment of compoundXXXIII with an alkenyl or substituted alkenyl silane in the presence ofa Lewis acid catalyst as exemplified above followed by esterification ofthe carboxyl group and subsequent removal of the N-phthaloyl protectinggroup as described above gives the desired intermediate. The alkenylmoiety may be hydrogenated to give the desired intermediate wherein R₆is alkyl or substituted alkyl of 3 to 7 carbons. When R₆ is other thanalkenyl or substituted alkenyl, treatment of compound XXXIII with thecorresponding R₆ containing organometallic compound in the presence of aLewis acid catalyst followed by esterification of the carboxyl group andsubsequent removal of the N-phthaloyl protecting group gives the desiredintermediate.

The intermediates of formula XV wherein X₁ is as defined in formula III,q is one, two, or three, R₇ is hydrogen, and R₆ is other than hydrogencan also be prepared according to the following process which is alsopart of this invention.

The N-phthalimido α-amino acid of formula XXIX can be converted to anester such as a benzyl or benzhydryl ester and then oxidized by treatingwith oxalyl chloride, dimethylsulfoxide, and triethylamine to give thealdehyde of the formula (XXXIV) ##STR48## wherein R₃₀ is benzyl orbenzhydryl.

Treatment of the aldehyde of formula XXXIV with an alkenyl orsubstituted alkenyl silane in the presence of a Lewis acid catalyst oran organometalic reagent such as trialkylaluminum, alkyl magnesiumhalide, alkyl lithium, alkyl zinc, or the corresponding reagents for theother definitions of R₆ to give the alcohol of the formula (XXXV)##STR49##

The alcohol of formula XXXV can then be converted to the correspondingazide such as by treatment with carbon tetrabromide andtriphenylphosphine followed by lithium or sodium azide or treatment withp-toluenesulfonyl chloride and pyridine followed by lithium or sodiumazide. Hydrogenation reduces the azide function to a primary amine andremoves the benzyl or benzhydryl ester group. Treatment withethyl-3-(dimethylamino)propyl carbodiimide and hydroxybenzotriazolegives a mixture of (XXXVI) ##STR50## and (XXXVII) ##STR51##

The compound of either formula XXXVI or XXXVII can be treated to removethe N-phthaloyl protecting group and introduce the t-butoxycarbonylprotecting group in its place. Reaction with a compound of the formula(XXXVIII) ##STR52## wherein L is a leaving group such as chloro, bromo,or tolylsulfonyloxy in the presence of base followed by removal of thet-butoxycarbonyl protecting group gives the desired intermediates offormula XV wherein X₁ is as defined in formula III, q is one, two, orthree, R₇ is hydrogen and R₆ is alkyl or substituted alkyl.

In a modification of this process, the aldehyde of formula XXXIV whereinR₃₀ is an alkyl such as methyl can be treated with an alkenyl orsubstituted alkenyl silane in the presence of a Lewis acid or anorganometallic reagent such as trialkylaluminum, alkyl magnesium halide,alkyl lithium, alkyl zinc, or the corresponding reagents for the otherdefinitions of R₆ to give the alcohol of formula XXXV wherein R₆ isalkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl--(CH₂)_(m)--, substituted aryl--(CH₂)_(m) --, heteroaryl--(CH₂)_(m) --, orcycloalkyl--(CH₂)_(m) -- and R₃₀ is alkyl.

This alcohol can then be converted to the azide as described above andthe N-phthaloyl protecting group removed and replaced by at-butoxycarbonyl protecting group. Reduction of the azide to a primaryamine followed by ring closure gives a mixture of the compounds of theformulas (XXXIX) ##STR53## and (XL) ##STR54##

The compound of either formula XXXIX or XL can then be treated with acompound of formula XXXVIII in the presence of base followed by removalof the t-butoxycarbonyl protecting group to give the desiredintermediates.

A further modification of these processes can be employed to give theintermediates of formula XV wherein X₁ is as defined in formula III, qis one, two, or three, and R₆ and R₇ are both other than hydrogen.

According to this modification, the alcohol of formula XXXV can beoxidized such as by treatment with oxalyl chloride, dimethylsulfoxide,and triethylamine to give the ketone of the formula (XLI) ##STR55##

The ketone of formula XLI can then be reacted with an alkenyl orsubstituted alkenyl silane in the presence of a Lewis acid or with anorganometallic reagent such as trialkylaluminum, alkyl magnesium halide,alkyl lithium, alkyl zinc, or the corresponding reagents for the otherdefinitions of R₇ to give the alcohol of the formula (XLII) ##STR56##

The alcohol of formula XLII can then be converted to the azide,hydrogenated to reduce the azide to an amine, and treated to effect ringclosure yielding the compound of the formula (XLIII) ##STR57##

The compound of formula XLIII can be treated to remove the N-phthaloylprotecting group and introduce a t-butoxycarbonyl or triphenylmethylprotecting group in its place followed by reacting with the compound offormula XXXVIII in the presence of base and removal of thet-butoxycarbonyl or triphenylmethyl protecting group.

The intermediates of formula XV wherein X₁ is as defined in formula IXor X, Y₂ is --CH₂ -- and v is two can be prepared according to thefollowing process which is also part of this invention.

The N-phthalimido α-amino acid of the formula (XLIV) ##STR58## iscoupled with the α-amino acid ester of the formula (XLV) ##STR59## inthe presence of a coupling catalyst as described above to give thealcohol of the formula (XLVI) ##STR60##

The alcohol of formula XLVI is oxidized such as by treatment with oxalylchloride, dimethylsulfoxide, and triethylamine to give the correspondingaldehyde which is then treated with an acid such as trifluoroacetic acidor hydrochloric acid to give the carboxylic acid ester of the formula(XLVII) ##STR61##

Cyclization of the compound of formula XLVII with a strong acid such astrifluoromethanesulfonic acid followed by reesterification byconventional means and treatment with sodium iodide gives a mixture ofthe compounds of the formulas (XLVIII) ##STR62## and (XLIX) ##STR63##

Removal of the N-phthaloyl protecting group from the intermediate offormula (XLIX) as described above gives the desired compound of formulaXV wherein X₁ is as defined in formula X and Y₂ is --CH₂ --.

Treatment of the intermediate of formula XLVIII withtris(trimethylsilyl) silane or tri-n-butyltin hydride in the presence ofa catalytic amount of azobisisobutyronitrile removes the iodo group. TheN-phthaloyl group is subsequently removed as described above to give thedesired compound of formula XV wherein X₁ is as defined in formula IX, vis two, and Y₂ is --CH₂ --. Similar procedure can be employed to givethe corresponding compound of formula XV wherein X₁ is as defined informula IX, v is one, and Y₂ is --CH₂ --.

In a variation of this process, the N-phthalimido α-amino acid offormula XLIV is reacted with the amino acid ester of the formula (L)##STR64## in the presence of a coupling catalyst as described above togive the dimethoxy compound of the formula (LI) ##STR65##

The compound of formula LI can then be treated with an acid such astrifluoroacetic acid or hydrochloric acid to give the carboxylic acidester of formula XLVII.

Other procedures for preparing the intermediates of formula XV appear inthe examples.

The compounds of formula I contain one or more asymmetric centers. Thus,these compounds can exist in diastereoisomeric forms or in mixturesthereof and all of such forms are within the scope of this invention.The above described processes can utilize racemates, enantiomers, ordiastereomers as starting materials. When diastereomeric compounds areprepared, they can be separated by conventional chromatographic orfractional crystallization methods.

The compounds of formula I wherein R₁₂ is hydrogen can be isolated inthe form of a pharmaceutically acceptable salt. Suitable salts for thispurpose are alkali metal salts such as sodium and potassium, alkalineearth metal salts such as calcium and magnesium, and salts derived fromamino acids such as arginine, lysine, etc. These salts are obtained byreacting the acid form of the compound with an equivalent of basesupplying the desired ion in a medium in which the salt precipitates orin aqueous medium and then lyophilizing.

The compounds of formula I are dual inhibitors possessing the ability toinhibit both the angiotensin converting enzyme and neutralendopeptidase. Thus, the compounds of formula I including theirpharmaceutically acceptable salts are useful in the treatment ofphysiological conditions in which either angiotensin converting enzymeinhibitors or neutral endopeptidase inhibitors have been shown to beuseful. Such conditions include cardiovascular diseases, particularly,hypertension, congestive heart failure, renal failure, and hepaticcirrhosis, as well as analgesic activity. Diuresis, natriuresis, andblood pressure reduction are produced in a mammalian host such as man bythe administration of from about 1 mg. to about 100 mg. per kg. of bodyweight per day, preferably from about 1 mg. to about 50 mg. per kg. ofbody weight per day, of one or more of the dual inhibitors of formula Ior a pharmaceutically acceptable salt thereof. The dual inhibitors offormula I are preferbly administered orally, but parenteral routes suchas subcutaneous, intramuscular, and intravenous can also be employed.The daily dose can be administered singly or can be divided into two tofour doses administered throughout the day.

The dual inhibitors of formula I can be administered in combination withhuman ANF 99-126. Such combination would contain the inhibitor offormula I at from about 1 to about 100 mg. per kg. of body weight andthe human ANF 99-126 at from about 0.001 to about 0.1 mg. per kg. ofbody weight.

The dual inhibitors of formula I can be administered in combination withother classes of pharmaceutically active compounds. For example, acalcium channel blocker, a potassium channel activator, a cholesterolreducing agent, etc.

The dual inhibitors of formula I or a pharmaceutically acceptable saltthereof and other pharmaceutically acceptable ingredients can beformulated for the above described pharmaceutical uses. Suitablecompositions for oral administration include tablets, capsules, andelixirs, and suitable compositions for parenteral administration includesterile solutions and suspensions. About 10 to 500 mg. of activeingredient is compounded with physiologically acceptable vehicle,carrier, excipient, binder, preservative, stabilizer, flavoring, etc.,in a unit dose form as called for by accepted pharmaceutical practice.

Preferred compounds of this invention with respect to the mercaptocontaining sidechain portion of formula I, i.e. ##STR66## include thosewherein: R₁ is hydrogen, ##STR67## or R₁₈ --S--, R₃ is lower alkyl of 1to 4 carbons or phenyl,

R₁₈ is lower alkyl of 1 to 4 carbons,

n is zero or one,

R₂ is aryl--CH₂ --, substituted aryl--CH₂ --, heteroaryl--CH₂ --, orstraight or branched chain alkyl of 1 to 7 carbons, and

R₁₉ is hydrogen.

Most preferred are the above mercapto containing sidechains wherein:

R₁ is hydrogen or ##STR68## especially hydrogen; n is zero; and

R₂ is benzyl, (2-thienyl)methyl, or straight or branched chain alkyl of1 to 5 carbons, especially benzyl.

Preferred compounds of this invention with respect to X₁ include thoseof formula III wherein:

q is one or two;

R₄ is hydrogen, methyl, or phenyl;

R₅ is hydrogen;

R₆ and R₇ are both hydrogen or are both methyl, or R₆ is lower alkyl of1 to 4 carbons, mono substituted lower alkyl of 1 to 4 carbons, oralkenyl of 3 to 5 carbons having one double bond and R₇ is hydrogen orR₆ and R₇ taken together with the carbon to which they are attachedcomplete a cycloalkyl of 3 to 5 carbons;

R₁₀ and R₁₁ are both hydrogen or one is hydrogen and the other is loweralkyl of 1 to 4 carbons;

b is zero or one; and

R₁₂ is hydrogen or lower alkyl of 1 to 4 carbons.

Most preferred are the above compounds of formula III wherein:

q is two;

R₄ and R₅ are both hydrogen;

R₆ and R₇ are both methyl or R₆ is methyl, propyl, allyl, or2-hydroxyethyl and R₇ is hydrogen;

b is zero;

R₁₀ and R₁₁ are both hydrogen or one is hydrogen and the other ismethyl; and

R₁₂ is hydrogen.

Preferred compounds of this invention with respect to X₁ include thoseof formula IV wherein:

r is one;

s is zero;

R₈ is hydrogen, phenyl, or lower alkyl of 1 to 4 carbons;

R₉ is hydrogen;

R₆ and R₇ are both hydrogen or are both methyl and R₆ is lower alkyl of1 to 4 carbons or phenyl and R₇ is hydrogen;

R₁₀ and R₁₁ are both hydrogen or one is hydrogen and the other is loweralkyl of 1 to 4 carbons;

b is zero; and

R₁₂ is hydrogen or lower alkyl of 1 to 4 carbons.

Most preferred are the above compounds of formula IV wherein:

R₈ is hydrogen or phenyl;

R₆ and R₇ are both hydrogen or R₆ is phenyl and R₇ is hydrogen;

R₁₀, R₁₁ and R₁₂ are all hydrogen.

Preferred compounds of this invention with respect to X₁ include thoseof formula V wherein:

s is zero;

t is one or two;

R₆ and R₇ are both hydrogen or are both methyl or R₆ is lower alkyl of 1to 4 carbons or phenyl and R₇ is hydrogen;

R₁₀ and R₁₁ are both hydrogen or one is hydrogen and the other is loweralkyl of 1 to 4 carbons;

b is zero; and

R₁₂ is hydrogen or lower alkyl of 1 to 4 carbons.

Most preferred are the above compounds of formula V wherein:

t is two;

R₆ is phenyl and R₇ is hydrogen; and

R₁₀, R₁₁, and R₁₂ are all hydrogen.

Preferred compounds of this invention with respect to X₁ include thoseof formula VI wherein:

Y₁ is O, S, or CH₂ ;

R₆ and R₇ are both hydrogen or R₆ is lower alkyl of 1 to 4 carbons andR₇ is hydrogen;

R₁₀ and R₁₁ are both hydrogen or one is hydrogen and the other is loweralkyl of 1 to 4 carbons;

b is zero; and

R₁₂ is hydrogen or lower alkyl of 1 to 4 carbons.

Most preferred are those above compounds of formula VI wherein:

Y₁ is CH₂ ;

R₆ and R₇ are both hydrogen; and

R₁₀, R₁₁, and R₁₂ are all hydrogen.

Preferred compounds of this invention with respect to X₁ include thoseof formula VII wherein:

Y₄ is --CH₂ --;

R₆ and R₇ are both hydrogen;

R₁₀ and R₁₁ are both hydrogen or one is hydrogen and the other is loweralkyl of 1 to 4 carbons, especially where both are hydrogen;

b is zero, and

R₁₂ is hydrogen or lower alkyl of 1 to 4 carbons, especially hydrogen.

Preferred compounds of this invention with respect to X₁ include thoseof formula VIII wherein:

R₆ and R₇ are both hydrogen or one is hydrogen and the other is loweralkyl of 1 to 4 carbons;

R₁₀ and R₁₁ are both hydrogen or one is hydrogen and the other is loweralkyl of 1 to 4 carbons, especially where both are hydrogen;

b is zero, and

R₁₂ is hydrogen or lower alkyl of 1 to 4 carbons, especially hydrogen.

Preferred compounds of this invention with respect to X₁ include thoseof formula IX wherein

v is one or two; especially two,

w is one or two;

Y₂ is S or CH₂ ; and

R₁₂ is hydrogen or lower alkyl of 1 to 4 carbons, especially hydrogen.

Preferred compounds of this invention with respect to X₁ include thoseof formula X wherein:

Y₂ is CH₂ ;

w is one or two, especially two; and

R₁₂ is hydrogen or lower alkyl of 1 to 4 carbons, especially hydrogen.

Preferred compounds of this invention with respect to X₁ include thoseof formula XI wherein:

v is one or two, especially two;

Z is O or two hydrogens, especially two hydrogens; and

R₁₂ is hydrogen or lower alkyl of 1 to 4 carbons, especially hydrogen.

Preferred compounds of this invention with respect to X₁ include thoseof formula XII wherein:

Z is O or two hydrogens, especially O;

R₁₇ is lower alkyl of 1 to 4 carbons, especially methyl;

R₁₀ and R₁₁ are both hydrogen or one is hydrogen and the other is loweralkyl of 1 to 4 carbons, especially where both are hydrogen;

b is zero; and

R₁₂ is hydrogen or lower alkyl of 1 to 4 carbons, especially hydrogen.

Preferred compounds of this invention with respect to X₁ include thoseof formula XIII wherein:

Y₃ is CH₂ or S, especially CH₂ ;

R₁₃ is hydrogen;

R₁₀ and R₁₁ are both hydrogen or one is hydrogen and the other is loweralkyl of 1 to 4 carbons, especially where both are hydrogen;

b is zero; and

R₁₂ is hydrogen or lower alkyl of 1 to 4 carbons, especially hydrogen.

The following examples are illustrative of the invention. Temperaturesare given in degrees centigrade. Thin layer chromatography (TLC) wasperformed in silica gel unless otherwise stated.

EXAMPLE 1 3R(S*)!-3,4-Dihydro-3-2-(mercaptomethyl)-1-oxo-3-phenylpropyl!amino!-4-oxo-1,5-benzothiazepine-5(2H)-aceticacid

a) (S)-2- (Acetylthio)methyl!benzenepropanoic acid, ephedrine salt

A solution of (1R, 2S)-(-)-ephedrine (17.3 g., 105 mmol.) in diethylether (175 ml.) was added in one portion to a solution of 2-(acetylthio)-methyl!benzenepropanoic acid (50.0 g., 210 mmol.) indiethyl ether (175 ml.). After standing at room temperature for 16hours, the crystallized ephedrine salt was collected by filtration (19.7g.); m.p. 114°-125°; α!D=-40.6° (c=1, methanol). An additional amount ofsolid 8.9 g., m.p. 121°-126°; α!_(D) =-47.2°, (c=1, methanol)! separatedfrom the filtrate after remaining at room temperature for 20 hours. Thesolids were combined and recrystallized from acetonitrile (1500 ml.).After 16 hours at room temperature, 20.8 g. of solid was collected; m.p.125°-130° C.; α!_(D) =-47.5° (c=1, methanol). This material wasrecrystallized in the same manner from acetonitrile (300 ml.) to give18.74 g., m.p. 128°-130° C.; α!_(D) =-48.9° (c=1, methanol). A thirdrecrystallization from acetonitrile (225 ml.) afforded 17.4 g. of solid(S)-2- (acetylthio)methyl!-benzenepropionic acid, ephedrine salt; m.p.128°-1290; α!_(D) =150.1° (c=1, methanol).

Anal. calc'd. for C₁₂ H₁₄ O₃ S.C₁₀ H₁₅ NO: C,65.48; H,7.24; N,3.47;S,7.95; Found: C,65.46; H,7.34; N,3.21; S,8.00.

b) 3R(S*)!-3,4-Dihydro-3- 2-(acetylthio)methyl!-1-oxo-3-phenylpropyl!amino-4-oxo-1,5-benzothiazepine-5(2H)-aceticacid, ethyl ester

(S)-2- (Acetylthio)methyl!benzenepropanoic acid, ephedrine salt (3.34mmoles, 1.01 eq.) was suspended in ethyl acetate (65 ml.), washed withdilute HCl (65 ml. water+4.7 ml. 1.0N hydrochloric acid then 31 ml.water +1.6 ml. 1.0N hydrochloric acid), brine (10 ml.), dried (anhydrousmagnesium sulfate), filtered and evaporated to dryness. The colorlesssyrup was dried in vacuo for 1.0 hour to afford a quantitative amount ofthe free acid (836 mg.).

The free acid was dissolved in dry dimethylformamide (19 ml.), cooleddown to 0° (ice-salt bath), treated with 1-hydroxybenztriazole hydrate(470 mg., 3.48 mmoles) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(690 mg., 3.60 mmoles) and stirred at 0° under argon for 1.0 hour. Theclear solution was treated with(R)-3,4-dihydro-3-amino-4-oxo-1,5-benzothiazepine-5(2H)-acetic acid,ethyl ester prepared according to the procedure of Slade et al., J. Med.Chem. 28, p 1517-1521 (1985)! (1.2 g., 3.32 mmoles) and4-methylmorpholine (0.37 ml., 3.32 mmoles) and stirring was continued at0° for 1.0 hour and at room temperature for 1.0 hour. The reactionmixture was diluted with ethyl acetate (80 ml.), washed successivelywith water (12 ml.), 5% potassium bisulfate (12 ml.), water (12 ml.),saturated sodium bicarbonate (12 ml.) and brine (12 ml.), dried(anhydrous magnesium sulfate), filtered, evaporated to dryness and driedin vacuo. The crude product was chromatographed on a silica gel column(Merck), eluting the column with ethyl acetate:hexanes (1:4) to give 1.5g. of the product as a syrup; R_(f) =0.68 (ethyl acetate:hexanes, 1:1).

c) 3P(S*)!-3,4-Dihydro-3-2-(mercaptomethyl)-1-oxo-3-phenylpropyl!amino!!-4-oxo-1,5-benzothiazepine-5(2H)-aceticacid

A solution of the ethyl ester product from part (a) (1.5 g., 2.996mmoles) in dry methanol (15 ml.) was purged with argon for 15 minutes,cooled down to 0° (ice-salt bath) then treated dropwise with apreviously purged (argon, 30 minutes) solution of 1.0N sodium hydroxide(12 ml., 4 eq.) maintaining the bubbling of argon throughout theaddition and the length of the reaction. The reaction mixture wasstirred at 0° for 1.0 hour, acidified at 0° with 5% potassium bisulfate(50 ml.) to pH 1.0 then extracted with ethyl acetate (2×100 ml.). Theorganic extract was washed with brine (25 ml.), dried (anhydrous sodiumsulfate), filtered, evaporated to dryness and dried in vacuo. The crudeproduct was dissolved in a mixture of methylene chloride (10 ml.) andethyl ether (5.0 ml.) then treated portionwise with hexane (30 ml.),scratching the mixture to form a solid. The precipitates were filteredoff, washed with hexane (50 ml.) and evaporated from pentane (4×50 ml.).The solid was then stirred with pentane (50 ml.) for 48 hours at roomtemperature under argon, filtered and dried in vacuo for 6 hours to give1.01 g. of the product as an amorphous solid; R_(f) =0.62 (methylenechloride:methanol:acetic acid, 20:1:1); α!_(D) =-171.4° (c=0.74,methanol). 1H NMR (CDCl₃): 2.47-2.90 (m, 6H), 3.84 (dd, 1H), 4.13 (d,1H, J=17 Hz), 4.71 (m, 1H), 4.85 (d, 1H, J=17 Hz), 6.88-7.67 (m, 9H).

Anal. calc'd. for C₂₁ H₂₂ N₂ O₄ S₂ : C,58.59; H,5.15; N,6.51; S,14.89;SH,7.68 Found: C,58.55; H,5.35; N,6.20; S,14.56; SH,7.54.

EXAMPLE 2 R-(R*,S*)!-3,4-Dihydro-3-(2-mercapto-1-oxo-3-phenyl-pronyl)amino!-4-oxo-1,5-benzothiazepine-5(2H)-aceticacid

a) (S)-2-(Acetylthio)benzenepropanoic acid, dicyclohexylamine salt

Sodium nitrite (10.3 g., 280 mmol.) was added to a solution ofD-phenylalanine (30.0 g., 181 mmol.) and potassium bromide (73.5 g.) insulfuric acid (2.5N, 365 ml.) over a period of one hour whilemaintaining the temperature of the reaction mixture at 0° C. The mixturewas stirred for an additional hour at 0° C. and then for one hour atroom temperature. The reaction solution was extracted with ether, theether was back extracted with water, and the ether layer was dried oversodium sulfate. Ether was removed in vacuo, and distillation of the oilyresidue afforded 25.7 g. of (R)-2-bromo-3-benzenepropanoic acid; b.p.141° (0.55 mm of Hg.); α!_(D) =+14.5° (c=2.4, chloroform).

A mixture of thioacetic acid (7 ml., 97.9 mmol.) and potassium hydroxide(5.48 g., 97.9 mmol.) in acetonitrile (180.5 ml.) was stirred underargon at room temperature for 1 3/4 hours. The mixture was cooled in anice--bath, and a solution of (R)-2-bromo-3-benzenepropanoic acid (20.4g., 89 mmol.) in acetonitrile (20 ml.) was added over a ten minuteperiod. The reaction was stirred under argon at room temperature for 5hours, filtered, and the acetonitrile was removed in vacuo. The oilyresidue was redissolved in ethyl acetate and washed with 10% potassiumbisulfate and water. Removal of the ethyl acetate in vacuo afforded 19.6g. of crude product. The crude product was purified via itsdicyclohexylamine salt using isopropyl ether as solvent forcrystallization. An analytical sample of(S)-2-(acetylthio)benzenepropanoic acid, dicyclohexylamine salt wasprepared by recrystallization from ethyl acetate; m.p. 146°-147°; α!_(D)=-39.6° (c=1.39, chloroform).

Anal. calc'd. for C₁₁ H₁₂ O₃ S.C₁₂ H₂₃ N: C,68.11; H,8.70; N,3.45;S,7.91; Found: C,67.93; H,8.71; N,3.37; S,7.94.

b) R-(R*,S*)!-3,4-Dihydro-3-2-(acetylthio)-1-oxo-3-phenylpropyl!amino!-4-oxo-1,5-benzothiazepine-5(2H)-aceticacid, ethyl ester

A suspension of (S)-2-(acetylthio)benzenepropanoic acid,dicyclohexylamine salt (1,76 g., 4.34 mmoles, 1.01 eq.) was suspended inethyl acetate (123 ml.), washed with 5% potassium bisulfate (5×19 ml.)and brine (25 ml.), dried (anhydrous magnesium sulfate), filtered,evaporated to dryness and dried in vacuo.

The free acid was dissolved in dry methylene chloride (25 ml.), cooleddown to 0° (ice-salt bath), treated with 1-hydroxybenztriazole hydrate(611 mg. 4.52 mmoles) and1-ethyl-3-(3-(dimethylaminopropyl)-carbodiimide (897 mg., 4.68 mmoles)and stirred at 0° for 1.0 hour. The solution was treated with(R)-3,4-dihydro-3-amino-4-oxo-1,5-benzothiazepine-5(2H)-acetic acid,ethyl ester prepared according to the procedure of Slade et al., J. Med.Chem., Vol. 28, p 1517-1521(1985)! (1.55 g., 4.29 mmoles) and4-methylmorpholine (0.48 ml., 4.37 mmoles) and stirring was continued at0° for 1.0 hour and at room temperature for 1.0 hour. The reactionmixture was diluted with ethyl acetate (104 ml.), washed successivelywith water (16 ml.), 5% potassium bisulyfate (2×16 ml.), saturatedsodium bicarbonate (16 ml.) and brine (16 ml.), dried (anhydrousmagnesium sulfate), filtered, evaporated to dryness and dried in vacuo.The crude product was chromatographed on a silica gel column (Merck),eluting the column with ethyl acetate:hexane (1:4) to give 1.347 g. ofproduct as a syrup; R_(f) =0.80 (ethyl acetate:hexane, 1:1).

c) R-(R*,S*)!-3,4-Dihydro-3-(2-mercapto-1-oxo-3-phenylpropyl)amino!-4-oxo-1,5-benzothiazepine-5(2H)-aceticacid

A solution of the ethyl ester product of part (b) (1.347 g., 2.768mmoles) in methanol (14 ml.) was purged with argon for 30 minutes,cooled down to 0° (ice-salt bath) then treated dropwise with apreviously purged (argon, 30 minutes) solution of 1.0N sodium hydroxide(11 ml., 4 eq.) maintaining the bubbling of argon throughout theaddition and the length of the reaction. The reaction mixture wasstirred at 0° for 1.0 hour, acidified at 0° with 5% potassium bisulfate(46 ml.) to pH 2.0 then extracted with ethyl acetate (2×100 ml.). Theorganic extracts were washed with brine (25 ml.), dried (anhydroussodium sulfate), filtered. evaporated to dryness and dried in vacuo. Thecrude product was dissolved in methylene chloride (10 ml.) and treatedportionwise with hexane (50 ml.), scratching the mixture to form asolid. The supernatant was decanted and the solids triturated withadditional hexane (50 ml.) and pentane (2×100 ml.), stirring with thefirst 100 ml. of pentane for 4 hours and the next 100 ml. overnightunder argon. The product obtained was then dried in vacuo for 12 hoursto give 1.048 g. of product as an amorphous solid; R_(f) =0.57(methylene chloride:methanol: acetic acid, 20:1:1); α!_(D) =-169.9°(c=0.61, methanol). 1H NMR (CDCl₃): 1.99(d,1H), 2.76 (t, 1H, J=11Hz),3.10 (m, 2H), 3.54 (m, 1H), 3.76 (m, 1H), 4.10 (d, 1H, J=17 Hz) 4.65 (m,1H), 4.86 (d, 1H, J=17 Hz), 7.12-7.68 (m, 9H).

Anal. calc'd for C₂₀ H₂₂ N₂ O₄ S.0.17 C₅ H₁₂. 0.52 H₂ O: C,57.15;H,5.30; N,6.40; S,14.64; SH,7.55; Found: C,57.15; H,4.99; N,6.14;S,14.72; SH,8.02.

EXAMPLE 3 (S,S)-1,3,4,5-Tetrahydro-4-2-(mercaptomethyl)-1-oxo-3-phenylpropyl!amino!-3-oxo-2H-2-benzazepine-2-aceticacid

a) N-(N-Phthaloyl-L-phenylalanyl)glycine, ethyl ester

Hydroxybenztriazole hydrate (1.42 g., 10.5 mmol.) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.10 g.,11.0 mmol) were added to a solution of N-phthaloyl-L-phenylalaninamide(2.95 g., 10.0 mmol.) in dry methylene chloride (30 ml.) at 0° underargon. After stirring at 0° C. for 30 minutes, the resulting mixture wastreated with glycine, ethyl ester, hydrochloride (1.675 g., 12.0 mmol.)and N-methylmorpholine (1.32 ml., 12.0 mmol). After stirring at 0° C.for 1 hour and at room temperature for 3 hours, the mixture waspartitioned between ethyl acetate-5% potassium bisulfate. The organicphase was washed successively with 5% potassium bisulfate, saturatedsodium bicarbonate and saturated sodium chloride solutions; dried(sodium sulfate) and evaporated to dryness. Trituration of the crudeproduct with ethyl ether gave 3.542 g. of product as a white,crystalline solid; m.p 158°-159° C.; R_(f) =0.33 (acetone:hexane, 2:3);α!_(D) =99.7° (c=0.61, chloroform).

b) (S)-1,3,4,5-Tetrahydro-4-phthalimido-3-oxo-2H-2-benzazepine-2-aceticacid, ethyl ester

A mixture of phosphorus pentoxide (9.6 g, 68 mmol) and 85% phosphoricacid (6.0 ml) was heated with stirring until all of the phosphoruspentoxide had dissolved. The resulting viscous liquid was taken up inglacial acetic acid (36 ml), treated successively withN-(N-phthaloyl-L-phenylalanyl)glycine, ethyl ester (2.241 g., 5.90mmol.) and trioxane (0.75 g., 8.3 mmol.), and heated at 80° C. (bathtemperature) under an argon atmosphere. After stirring at 80° C. for 6.5hours the mixture was treated with an additional portion of trioxane(0.75 g, 8.3 mmol). After stirring at 80° C. for an additional 16 hours,the reaction was quenched with an ice-water mixture and extracted withethyl acetate. The ethyl acetate extract was washed with water (3X),saturated sodium bicarbonate (until washes were basic) and saturatedsodium chloride solutions, dried (sodium sulfate) and evaporated todryness. The crude product was purified by flash chromatography onsilica gel (Whatmann LPS-1) eluting with ethyl acetate-hexane (35:65) togive 1.718 g. of product as a colorless foam; R_(f) =0.38 (ethylacetate:toluene, 3:7).

c) (S)-1,3,4,5-Tetrahydro-4-(phenylmethoxy)-carbonyl!amino!-3-oxo-2H-2-benzazepine-2-acetic acid,ethyl ester

A solution of(S)-1,3,4,5-tetrahydro-4-phthalimido-3-oxo-2H-2-benzazepine-2-aceticacid, ethyl ester (1.67 g., 4.26 mmol.) in 1.0M hydrazine hydrate inethanol (9.0 ml., 9.0 mmol.) was stirred at room temperature under argonfor 36 hours. The mixture was diluted with an equal volume of ethylacetate, filtered and filtrate evaporated to dryness. The residue wastaken up in toluene and again evaporated to dryness. The colorless,semi-solid residue (1.81 g.) was taken up in dry methylene chloride (20ml.), placed in an ice bath and treated successively with triethylamine(0.80 ml., 5.8 mmol.) and benzylchloroformate (0.77 ml., 5.4 mmol.).After stirring at 0° C. for 2 hours, the mixture was partitioned betweenethyl acetate-5% potassium bisulfate. The organic phase was washedsuccessively with 5% potassium bisulfate, saturated sodium bicarbonateand saturated sodium chloride solutions, dried (sodium sulfate), andevaporated to dryness. Purification of the crude product by flashchromatography on silica gel (Whatmann LPS-1) eluting with ethylacetate:hexane (1:2) gave 1.0747 g. of product as a colorless foam;R_(f) =0.52 (ethyl acetate:toluene, 3:7). A sample crystallized fromhexane had m.p. 80°-82° C.; α!_(D) =+87.2° (c=0.53, chloroform).

d) (S)-1,3,4,5-Tetrahyvdro-4-amino-3-oxo-2H-2-benzazepine-2-acetic acid,ethyl ester

20% Palladium hydroxide/carbon catalyst was added to a solution of(S)-1,3,4,5-tetrahydro-4-(phenylmethoxy)carbonyl!amino!-3-oxo-2H-2-benzazepine-2-acetic acid,ethyl ester (1.037 g., 2.62 mmole) in absolute ethanol (20 ml.) and theesulting suspension was stirred under a hydrogen atmosphere (balloon)for 2 hours. The mixture was filtered through Celite and filtrate wasevaporated to dryness. The semi-solid residue was triturated with hexaneto give 0.63 g. of product as a white, crystalline solid; m.p. 71°-73°C.; R_(f) =0.38 (methanol:methylene chloride, 1:9); α!_(D) =77.5°(c=0.59, chloroform).

e) (S,S)-1,3,4,5-Tetrahydro-4- 2-(acetylthio)-methyl!-1-oxo-3-phenylpropyl!amino!-3-oxo-2H-2-benzazepine-2-aceticacid, ethyl ester

(S)-2- (Acetylthio)methyl!benzenepropanoic acid, ephedrine salt (0.43g., 1.07 mmol.) was partitioned between ethyl acetate (20 ml.)-aqueoushydrochloric acid (1.5 ml. 1.0N hydrochloric acid+20 ml water). Theorganic phase was washed with aqueous hydrochloric acid (0.5 ml. 1.0Nhydrochloric acid +10 ml water) and saturated sodium chloride solutions,dried (sodium sulfate) and evaporated to dryness. The resulting freeacid (0.260 g., about 1.07 mmol) was taken up in dry dimethylformamide(6.0 ml.), placed in an ice bath and treated with hydroxybenztriazolehydrate (0.150 g, 1.11 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.220 g,1.15 mmol). After stirring at 0° C. for 1 hour, the resulting mixturewas treated with(S)-1,3,4,5-tetrahydro-4-amino-3-oxo-2H-2-benzazepine-2-acetic acid,ethyl ester (0.260 g, 0.992 mmol) in one portion. After stirring at 0°C. for 2 hours and at room temperature for 1 hour, the mixture waspartitioned between ethyl acetate-water. The organic phase was washedsuccessively with water, 5% potassium bisulfate, saturated sodiumbicarbonate and saturated sodium chloride solutions, dried (sodiumsulfate) and evaporated to dryness. Purification of the crude product(0.506 g.) by flash chromatography on silica gel (Whatmann LPS-1)eluting with ethyl acetate-hexane (35:65) gave 0.39 g. as a colorlessfoam; R_(f) =0.30 (ethyl acetate:hexane; 1:1).

f) (S,S)-1,3,4,5-Tetrahydro-4-2-(mercaptomethyl)-1-oxo-3-phenylpropyl!amino!-3-oxo-2H-2-benzazepine-2-aceticacid

A degassed solution of 1.0N aqueous sodium hydroxide (3.2 ml., 3.2mmol.) was added to a degassed solution of the ethyl ester product frompart (e) 0.39 g., 0.809 mmol.) in methanol (4 ml.) at 0° C. Throughoutthe course of the reaction, argon was continously passed into thereaction mixture. After stirring at 0° C. for 45 minutes the reactionwas quenched with 5% potassium bisulfate (20 ml.) and extracted withethyl acetate. The ethyl acetate extract was washed with 5% potassiumbisulfate and saturated sodium chloride solutions, dried (sodiumsulfate) and evaporated to dryness. The crude product was crystallizedwith ethyl acetate-hexane, collected by suction and dried in vacuo at50° C. to give 0.309 g, of product as a white solid, mp 149°-151° C.(decomp). R_(f) =0.47 (methylene chloride:acetic acid:methanol, 20:1:1);α!_(D) =+112.20 (c=0.58, methanol)

Anal. calc'd for C₂₂ H₂₄ N₂ O₄ S: C,64.06; H,5.86; N,6.79; S,7.77;SH,8.02; Found: C,64.20; H,6.09; N,6.43; S,7.68; SH,8.33.

EXAMPLE 4 (S,S)-1,3,4,5-Tetrahydro-4-(2-mercapto-1-oxo-3-phenylpropyl)amino!-3-oxo-2H-2-benzazepine-2-aceticacid

a) (S,S)-1,3,4,5-Tetrahydro-4-2-(acetylthio)-1-oxo-3-phenylpropyl!amino!-3-oxo-2H-2-benzazepine-2-aceticacid, ethyl ester

(S)-2-(Acetylthio)benzenepropanoic acid, dicyclohexylamine salt (0.532g., 1.31 mmol.) was partitioned between ethyl acetate-5% potassiumbisulfate (25 ml. each). The organic phase was washed with 5% potassiumbisulfate (2×15 ml) and saturated sodium chloride solutions, dried(sodium sulfate) and evaporated to dryness. The resulting free acid(colorless oil) was taken up in dry dimethylformamide (6.0 ml.), placedin an ice bath and treated with hydroxybenztriazole hydrate (0.185 g.,1.37 mmol) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimidehydrochloride (0.270 g, 1.41 mmol). After stirring at 0° C. for 45minutes, the resulting mixture was treated with(S)-1,3,4,5-tetrahydro-4-amino-3-oxo-2H-2-benzazepine-2-acetic acid,ethyl ester (0.32 g., 1.22 mmol.) in one portion. After stirring at 0°C. for 2 hours and at room temperature for 1 hour, the mixture waspartitioned between ethyl acetate-water. The organic phase was washedsuccessively with water, 5% potassium bisulfate, saturated sodiumbicarbonate and saturated sodium chloride solutions; dried (sodiumsulfate) and evaporated to dryness. TLC (ethyl acetate-hexane; 1:1)shows two products, R_(f's=) 0.35 (desired) and 0.28 (epimer).Purification by flash chromatography on silica gel (Whatmann LPS-1)eluting with ethyl acetate-hexane (1:2) gave 0.357 g. of product as acolorless foam; R_(f) =0.35 (ethyl acetate:hexane, 1:1).

b) (S,S)-1,3,4,5-Tetrahydro-4-(2-mercapto-1-oxo-3-phenylpropyl)amino!-3-oxo-2H-2-benzazepine-2-aceticacid

A degassed solution of 1.0N aqueous sodium hydroxide (3.1 ml., 3.1mmol.) was added to a degassed solution of the ethyl ester product frompart (a) (0.357 g., 0.763 mmol.) in methanol (4 ml.) at 0° C. Throughoutthe course of the reaction, argon was continously passed into thereaction mixture. After stirring at 0° C. for 45 minutes, the reactionwas quenched with 5% potassium bisulfate (25 ml) and extracted withethyl acetate. The ethyl acetate extract was washed with 5% potassiumbisulfate and saturated sodium chloride solutions, dried (sodiumsulfate) and evaporated to dryness. The crude product was trituratedwith ethyl ether-hexane, collected by suction and dried in vacuo at 50°C. to give 0.290 g. as a white solid; m. p. 181°-183° C.(decomposition); R_(f) =0.49 (methylene chloride:acetic acid:methanol,20:1:1); α!_(D) =+103.40 (c=0.57, methanol).

Anal. calc'd for C₂₁ H₂₂ N₂ O₄ S: C,63.30; H,5.56; N,7.03; S,8.05;SH,8.30; Found C,63.35; H,5.65; N,6.87; S,8.07; SH,9.40.

EXAMPLE 5 S-(R*,R*)!-2,3,4,5-Tetrahydro-3-2-(mercapto-methyl)-1-oxo-3-phenylpropyl!amino!-2-oxo-1H-benzazepine-1-aceticacid

a) S-(R*,R*)!-2,3,4,5-Tetrahydro-3- 2-(acetylthio)methyl!-1-oxo-3-phenylpropyl!amino!-2-oxo-1H-benzazepine-1-aceticacid, ethyl ester

(S)-2- (Acetylthio)methyl!benzenepropanoic acid, ephedrine salt (1.547g., 3.83 mmoles, 1.01 eq.) was suspended in ethyl acetate (72 ml.),washed with dilute hydrochloric acid (72 ml. water+5.4 ml. 1.0Nhydrochloric acid then 36 ml. water+1.8 ml. 1.0N hydrochloric acid),brine (12 ml.), dried (anhydrous magnesium sulfate), filtered andevaporated to dryness. The colorless syrup was dried in vacuo for 1.0hour to give 1.062 g. of (S)-2- (acetylthio)methyl!benzenepropanoicacid.

The free acid was dissolved in dry dimethylformamide (21.8 ml.), cooleddown to 0° (ice-salt bath), treated with 1-hydroxybenztriazole hydrate(540 mg., 3.99 mmoles) and 1-ethyl-3-(3-dimethylaminopropylcarbodiimide(792 mg., 4.13 mmoles) and stirred at 0° under argon for 1.0 hour. Theclear solution was treated with(S)-2,3,4,5-tetrahydro-3-amino-2-oxo-1H-benzazepine-1-acetic acid, ethylester prepared as described by Watthey et al., J. Med. Chem., 28, p.1511-1516 (1985)! (1.0 g., 3.81 mmoles) and stirring was continued at 0°for 1.0 hour and at room temperature for 1.0 hour. The reaction mixturewas diluted with ethyl acetate (100 ml.), washed successively with water(15 ml.), 5% potassium bisulfate (2×15 ml.), saturated sodiumbicarbonate (15 ml.) and brine (15 ml.), dried (anhydrous magnesiumsulfate), filtered, evaporated to dryness and dried in vacuo. The crudeproduct was chromatographed on a silica gel column (Merck), eluting thecolumn with ethyl acetate:hexane mixtures (1:4; 1:2) to give 1.725 g. ofproduct as a syrup; R_(f) =0.42 (ethyl acetate:hexane, 1:1).

b) S-(R*,R*)!-2,3,4,5-Tetrahydro-3-2-(mercapto-methyl)-1-oxo-3-phenylpropyl!amino!-2-oxo-1H-benzazepine-1-aceticacid

A solution of the ethyl ester product from part (a) (1.725 g., 3.574mmoles) in methanol (18.0 ml.) was purged with argon for 30 minutes,cooled down to 0° (ice-salt bath) then treated dropwise with apreviously purged (argon, 30 minutes) solution of 1.0N sodium hydroxide(14.3 ml., 4 eq.) maintaining the bubbling of argon throughout theaddition and the length of the reaction. The reaction mixture wasstirred at 0° for 1.0 hour, acidified at 0° with 5% potassium bisulfate(60 ml.) to pH 1.0 then extracted with ethyl acetate (2×120 ml.). Theorganic extracts were washed with brine (30 ml.), dried (anhydroussodium sulfate), filtered, and evaporated to dryness. The crude productwas dissolved in methylene chloride (10 ml.) and treated portionwisewith hexane (50 ml.), scratching the mixture to form a solid. Thesupernatant was decanted and the solids triturated with additionalhexane (2×50 ml.) and pentane (2×100 ml.), stirring with the first 100ml. of pentane for 4.0 hours and the next 100 ml. overnight under argon.The product obtained was then dried in vacuo for 12 hours to give 1.438g. of product as an amorphous solid R_(f) =0.53 (methylenechloride:methanol:acetic acid, 20:1:1); α!_(D) =-140.4° (c=0.76,methanol)

Anal. calc'd for C₂₂ H₂₄ N₂ O₄ S.0.11 C₅ H₁₂ : C,64.42; H,6.07; N,6.66;S,7.63; SH,7.87; Found: C,64.07; H,6.13; N,6.34; S,7.25; SH,7.14.1NMR(CDCl₃) 1.42 (t, 1H), 1.95 (m, 1H), 2.44-2.90 (m, 7H), 3.27 (m, 1H),4.37 (d, 1H, J=17 Hz), 4.52 (m, 1H), 4.67 (d, 1H, J=17 Hz), 6.86-8.00(m, 9H).

EXAMPLE 6 S-(R*,R*)!-2,3,4,5-Tetrahydro-3-(2-mercapto-1-oxo-3-phenylpropyl)amino!-2-oxo-IH-benzazepine-1-aceticacid

a) S-(R*,R*)-2,3,4,5-Tetrahydro-3-2-(acetylthio)-2-oxo-3-phenylpropyl!amino!-2-oxo-1H-benzazepine-1-aceticacid, ethyl ester

A suspension of (S)-2-(acetylthio) benzenepropanoic acid,dicyclohexylamine salt (1.70 g., 4.19 mmoles) was suspended in ethylacetate (120 ml.), washed with 5% potassium bisulfate (5×20 ml.) andbrine (25 ml.), dried (anhydrous magnesium sulfate, filtered, evaporatedto dryness and dried in vacuo to give 954 mg. of the free acid as asyrup.

This free acid was dissolved in dry methylene chloride (25 ml.) andcooled down to 0° (ice-salt bath) treated with 1-hydroxybenztriazolehydrate (594 mg., 4.40 mmoles) and1-ethyl-3-(3-dimethyl-aminopropyl)carbodidimide (870 mg., 4.54 mmoles)and stirred at 0° for 1.0 hour. The solution was treated with a solutionof (S)-2,3,4,5-tetrahydro-3-amino-2-oxo-1H-benzazepine-1-acetic acid,ethyl ester prepared as described by watthey et al., J. Med. Chem., 28,p 1511-1516 (1985)! (1.0 g., 3.81 mmoles) in dry methylene chloride (10ml.) and stirring was continued at 0° for 1.0 hour and at roomtemperature for 1.5 hours. The reaction mixture was diluted with ethylacetate (100 ml.), washed successively with water (15 ml.), 5% potassiumbisulfate (2×15 ml.), saturated sodium bisulfate (15 ml.) and brine (15ml.), dried (anhydrous sodium sulfate), filtered, evaporated to drynessand dried in vacuo. The crude product was chromatographed on a silicagel column (Merck), eluting the column with ethyl acetate:hexanemixtures (1:4; 1:2) to give 1.632 g. of product as a syrup. Anadditional 127 mg. of the isomer mixture (1:1 ratio) was also obtainedfrom the column; R_(f) =0.50 (ethyl acetate:hexane, 1:1).

b) S-(R*,R*)!-2,3,4,5-Tetrahydro-3-(2-mercapto-1-oxo-3-phenylpropyl)amino!-2-oxo-1H-benzazepine-1-aceticacid

A solution of the ethyl ester product from part (a) (1.57 g., 3.35mmoles) in methanol (17.0 ml.) was purged with argon for 30 minutes,cooled down to 0° (ice-salt bath) then treated dropwise with apreviously purged (argon, 30 minutes) solution of 1.0N sodium hydroxide(13.4 ml., 4.0 eq.) maintaining the bubbling of argon throughout theaddition and length of the reaction. The reaction mixture was stirred at0° for 1.0 hour, acidified at 0° with 5% potassium bisulfate (60 ml.) topH 1.0 then extracted with ethyl acetate (2×110 ml.). The organicextracts were washed with brine (30 ml.), dried (anhydrous sodiumsulfate), filtered, evaporated to dryness and dried in vacuo. The crudeproduct was dissolved in methylene chloride (10 ml.) and treatedportionwise with hexane (50 ml.), scratching the mixture to form asolid. The supernatant was decanted and the solids triturated withadditional hexane (2×50 ml.) and pentane (2×100 ml.), stirring with thefirst 100 ml. of pentane for 4 hours and the next 100 ml. overnightunder argon. The product obtained was then dried in vacuo for 12 hoursto give 1.237 g. of product; R_(f) =0.58 (methylenechloride:methanol:acetic acid, 20:1:1); α!_(D) =-155.5° (c=0.73,methanol).

Anal.calc'd.for C₂₁ H₂₂ N₂ O₄ S.0.1 C₅ H₁₂.0.18 H₂ O: C,63.14; H,5.81;N,6.85; S,7.84; SH,8.09; Found: C,63.14; H,5.85; N,6.58; S,7.50;SH,7.05. 1H-NMR-(CDCl₃): 1.88 (m, 1H), 1.97 (d,1H), 2.62 (m,2H), 3.07(m, 2H), 3.25 (m, 1H), 3.51 (m, 1H), 4.39 (d, 1H, J=17 Hz), 4.45 (m,1H), 4.64 (m, 1H, J=17 Hz), 7.07-7.41 (m, 9H).

EXAMPLE 7 2S- 2α, 5α(R*)!!-5,6-Dihydro-5-(2-mercapto-1-oxo-3-phenylpropyl!amino!-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-aceticacid

a)(2S-cis)-5,6-Dihydro-5-phthalimido-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-aceticacid, ethyl ester

Following the procedure of U.S. Pat. No. 4,460,579 Example 1(a) through1(c), 15.6 g., of the diastereomeric product mixture was obtained. Themixture was refluxed in ether (500 ml.) for 4 hours, cooled in anice-bath, and filtered to yield 5.9 g. of(2R-trans)-5,6-dihydro-5-phthalimido-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-aceticacid, ethyl ester; m.p. 166°-168° C.; R_(f) =0.40 (hexanes:ethylacetate, 1:1); α!_(D) =-72.9° (c=1, chloroform).

Anal. calc'd. for C₂₂ H₂₀ O_(N) ₂ O₅ S: C,62.25; H,4.75; N,6.60; S,7.77;Found: C,62.21; H,4.82; N,6.63; S,7.52.

Trituration of the remainder of the product mixture with refluxing ether(125 ml.) afforded a second batch of 0.9 g. of the (2R-trans) isomerproduct. The residue was triturated again with refluxing ether to give0.75 g. of insoluble substance largely (2R-trans) isomer! and 7.1 g. ofmaterial enriched in (2S-cis) isomer. 6.0 g. of the enriched (2S-cis)isomer material was chromatographed on two connected Waters Prep L Ccolumns and eluted with hexanes:ethyl acetate (3:1). Pooling of theproduct containing fractions yielded 4.8 g. of(2S-cis)-5,6-dihydro-5-phthalimido-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-aceticacid, ethyl ester, m. p. 66-68° C.; α!_(D) =-101.2°. TLC same as isomerA.

Anal. calc'd. for C₂₂ H₂₀ N₂ O₅ S.0.2 H₂ O: C,61.83; H,4.79; N,6.55;S,7.50; Found: C,61.83; H,5.07; N,6.25; S,7.42.

b)(2S-cis)-5,6-Dihydro-5-amino-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-aceticacid, ethyl ester

A solution of the (2S-cis) isomer product from part (a) (approximately85% diastereomerically pure, 3.03 g., 7.1 mmol.) in chloroform (15 ml.)was treated with methyl hydrazine (850 el., 736 mg., 16.0 mmol.). Afterstirring at room temperature for 24 hours, the mixture was diluted withethyl acetate and ethyl ether and filtered. The filtrate was extractedtwice with 0.5N hydrochloric acid and the pooled aqueous extracts weremade basic with 1N sodium hydroxide. The aqueous mixture was extractedthree times with methylene chloride and the pooled methylene chlorideextracts were dried (sodium sulfate), filtered, and stripped to give1.648 g., of product as a pale yellow oil; R_(f) =0.43 (methylenechloride:acetic acid:methanol, 8:1:1). NMR analysis showed the productwas obtained in approximately 84% diastereomeric purity.

c) 2S- 2α, 5α(R*)!!-5,6-Dihydro-5-2-(acetylthio)-1-oxo-3-phenylpropyl!amino!-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)aceticacid, ethyl ester

(S)-2-(Acetylthio)benzenepropanoic acid, dicyclohexylamine salt (1.318g., 3.25 mmol.) was partitioned between ethyl acetate and 5% potassiumbisulfate. The ethyl acetate layer was washed with water and brine, thendried (sodium sulfate), filtered and stripped to give the free acid as acolorless oil. A mixture of acid this free acid and the (2S-cis) productfrom part (b) (84% diastereomeric purity, 960 mg., 3.26 mmol.) wasdissolved in methylene chloride (25 ml.) and treated with1-hydroxybenztriazole hydrate (622 mg., 4.6 mmol.) then cooled to -10°C. The mixture was subsequently treated with1-ethyl-3-(3-dimethyl-aminopropyl)-carbodiimide (687 mg., 3.58 mmol.).After slowly warming to 0° C. over a one hour period, the mixture wassubsequently warmed to room temperature. After 4 hours, the solution wasdiluted with ethyl acetate and washed successively with water, 5%potassium bisulfate, water, saturated sodium bicarbonate, and brine,then dried (sodium sulfate), filtered, and stripped. The residue wasflash chromatographed (Merck silica gel, 1:1-ethyl acetate:hexane) togive 804 mg. of product as a colorless foam; R_(f) =0.33 (50% ethylacetate in hexanes). NMR analysis indicated the material was 91%diastereomerically pure with respect to acetylthio center.

d) 2S- 2α, 5α(R*)!!-5,6-Dihydro-5-(2-mercapto-1-oxo-3-phenylpropyl!amino!-4-oxo-2-phenyl-2H-3-thiazine-3(4H)-aceticacid

A solution of the ethyl ester product from part (c) (500 mg., 1.0 mmol.)in methanol (5 ml., deoxygenated via argon bubbling) at 0° C. wastreated with ice cold 1N sodium hydroxide (5 ml., deoxygenated via argonbubbling) and the resulting mixture was stirred at 0° C. under argon for30 minutes. The solution was acidified with 10% potassium bisulfate (15ml.), diluted with water and extracted with ethyl acetate. The ethylacetate extract was washed with water and brine, then dried (sodiumsulfate), filtered and stripped to afford an oil/foam. This material wasflash chromatographed (Merck silica gel, 20:1:1-methylenechloride:methanol:acetic acid). The fractions containing the productwere pooled and stripped, and the residue was taken up in ethyl acetateand washed successively with water, 0.5N hydrochloric acid, and brine,then dried (sodium sulfate), filtered and stripped again. The resultingoil was dissolved in a small amount of ethyl acetate and ethyl ether andtriturated with hexane. The mixture was stripped to dryness, slurried inhexane, stripped to dryness again, and dried in vacuo to give 392 mg.,of product as a white foam; R_(f) =0.24 (methylenechloride:methanol:acetic acid, 20:1:1); α!_(D) =-13.2° (c=0.5,chloroform). HPLC: YMC S3 ODS column (6.0×150 mm); eluted with 44% A:90% water-10% methanol-0.2% phosphoric acid and 56% B: 10% water-90%methanol-0.2% phosphoric acid; flow rate 1.5 ml/min detecting at 220 nm;t_(R) =26.22 min. and t_(R) =24.64 min (9.3% 5α(S*) isomer).

Anal. calc'd. for C₂₁ H₂₂ N₂ O₄ S₂.0.17H₂ O: C,58.18; H,5.19; N,6.46;S,14.79; SH,7.63; Found: C,58.20; H,5.51; N,6.44; S,14.46; SH,6.60.

EXAMPLE 8 2S- 2α, 5α(R*)!!-5,6-Dihydro-5-2-(mercaptomethyl)-1-oxo-3-phenylpropyl!amino!-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-aceticacid

a) 2S- 2α. 5α(R*)!!-5,6-Dihydro-5- -2-(acetylthio)-methyl!-1-oxo-3-phenylpropyl!amino!-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-aceticacid, ethyl ester

(S)-2- (Acetylthio)methyl!benzenepropanoic acid, ephedrine salt (1.638g., 4.04 mmol.) was partitioned between ethyl acetate and watercontaining 6.0 ml. 1N hydrochloric acid. The ethyl acetate layer waswashed with water and brine, then dried (sodium sulfate), filtered, andstripped to give the free acid as a colorless oil. A mixture of thisfree acid and(2S-cis)-5,6-dihydro-5-amino-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-aceticacid,ethyl ester 84% diastereomerically pure, 1.19 g., 4.04 mmol.) wasdissolved in methylene chloride (25 ml.) and treated with1-hydroxybenztriazole hydrate (575 mg, 4.2 mmol.) then cooled to 0° C.The mixture was subsequently treated with1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (775 mg, 4.04 mmol). Themixture was stirred at 0° C. for 45 minutes, then let warm to roomtemperature. After an additional 2 hours, the solution was diluted withethyl acetate and washed successively with water, 5% potassiumbisulfate, water, saturated sodium bicarbonate, and brine, then dried(sodium sulfate), filtered, and stripped. The residue was flashchromatographed (Merck silica gel, 40% to 60% ethyl acetate in hexane)to give 1.228 g., of product as a white foam; R_(f) =0.29 (50% ethylacetate in hexanes). NMR analysis indicated that the product wasdiastereomerically pure.

b) 2S- 2α, 5α(R*)!!-5,6-Dihydro-5-2-(mercaptomethyl)-1-oxo-3-phenylpropyl!amino!-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-aceticacid

A solution of the ethyl ester product from part (a) (705 mg., 1.37mmol.) in methanol, (10 ml. deoxygenated via argon bubbling) was treatedwith 1N sodium hydroxide (10 ml., deoxygenated via argon bubbling) andthe resulting mixture was stirred at 0° C. under argon for 15 minutes.The solution was acidified with 1N hydrochloric acid (15 ml.), dilutedwith water and extracted with ethyl acetate. The ethyl acetate extractwas washed with water and brine, then dried (sodium sulfate), filteredand stripped to afford an oil. The material was flash chromatographed(Merck silica gel, 20:1:1-methylene chloride:methanol: acetic acid). Thefractions containing the desired product were pooled, and stripped, andthe residue was taken up in ethyl acetate and washed successively withwater, 0.5N hydrochloric acid, and brine, then dried (sodium sulfate),filtered and stripped again. The resulting oil was dissolved in a smallamount of ethyl acetate and ethyl ether and triturated with hexane. Themixture was stripped to dryness, slurried in hexane, stripped to drynessagain, and dried in vacuo to give 548 mg. of product as a relativelyhard white foam; R_(f) =0.29 (methylene chloride:methanol:acetic acid,20:1:1); α!_(D) =+42.9° (c=1.0, chloroform). HPLC: YMC S3 ODS column(6.0×150 mm); eluted with 44% A: 90% water-10% methanol-0.2% phosphoricacic and 56% B: 10% water-90% methanol-0.2% phosphoric acid; flow rate1.5 ml/min detecting at 220 nm; t_(R) =33.45 min (99.1%).

Anal. calc'd. for C₂₂ H₂₄ N₂ O₄ S₂ : C,59.44; H,5.44; N,6.30; S,14.42;SH,7.44 Found: C,59.63; H,5.84; N,5.99; S,14.54; SH,6.83.

EXAMPLE 9 (S,S)-Hexahydro-3-2-(mercaptomethyl)-1-oxo-3-phenylpropyl!amino!-2-oxo-1H-azepine-1-aceticacid

a) N² - (1,1-Dimethylethoxy)carbonyl!-N⁶ -(phenylmethoxy)carbonyl!-L-lysine, methyl ester

Cesium carbonate (4.28 g., 13.1 mmoles) was added to a mixture of N² -(1,1-dimethylethoxy) carbonyl!-N⁶ - (phenylmethoxy)carbonyl!-L-lysine(10 g., 26.3 mmoles) and 20% water-methanol (60 ml.). The solutionbecame homogeneous within 5 minutes so the solvent was stripped and theresidual water removed azeotropically with acetonitrile (3x). Theresulting oil was dried in vacuo , dissolved in dry dimethyl-formamideand treated with methyl iodide (3.2 ml., 2.0 eq.). The reaction mixturewas stirred at room temperature for 1.5 hours under argon, diluted withethyl acetate (200 ml.) and washed successively with water (2×25 ml.),saturated sodium bicarbonate (25 ml.) and brine (25 ml.). The organicphase was dried (anhydrous magnesium sulfate), filtered, evaporated todryness and dried in vacuo to give 10.11 g., of product as a lightyellow syrup; R_(f) =0.30 (ethyl acetate:hexanes, 1:2).

b) (S)-3- (1.1-Dimethylethoxy)carbonyl!amino-hexahydro-2H-azepin-2-one

A solution of the methyl ester product from part (a) (8.532 g., 21.63mmoles) in dry methanol (100 ml.) was treated with 10% palladium oncarbon catalyst (2.13 g.) and hydrogenated at 50 psi for 2 hours. Themixture was diluted with methanol (100 ml.) and filtered through acelite pad in a millipore unit, washing the pad well with methanol(3×100 ml.). The clear filtrate was evaporated to dryness, dried invacuo and the resulting oil was dissolved in dry xylene (70 ml.). Thesolution was refluxed under argon for 20 hours, cooled down to roomtemperature, diluted with ethyl acetate (425 ml.), and washedsuccessively with 5% potassium bisulfate (85 ml.), saturated sodiumbicarbonate (85 ml.) and brine (85 ml.). The organic phase was dried(magnesium sulfate), filtered, evaporated to dryness and dried in vacuo.The crude product was chromatographed on a silica gel column (Merck),eluting the column with ethyl acetate:hexane (1:1) to give 2.76 g. ofproduct as a white solid; m. p. 146°-147°; R_(f) =0.58 (ethyl acetate);α!_(D) =+4.5° (c=1.0, methanol).

Anal. calc'd. for C₁₁ H₂₀ N₂ O₃ : C,57.87; H,8.83; N,12.27: Found:C,58.12; H,8,63; N,12,26.

c) (S)-3-(1,1-Dimethylethoxy)carbonyl!amino!-hexahydro-2-oxo-1H-azepine-1-aceticacid, ethyl ester

A suspension of the 2H-azepine-2-one product from part (b) (2.966 g.,12.99 mmoles) in dry tetrahydrofuran (21.0 ml.) was treated with 1.0Mpotassium t-butoxide/tetrahydrofuran (16.9 ml., 1.3 eq.) and stirredunder argon at room temperature for 5 minutes. The clear light brownsolution was treated dropwise with ethyl bromoacetate (2.34 ml., 1.7eq.), stirred at room temperature for 1.0 hour then diluted with ethylacetate (100 ml.). The mixture was washed with saturated sodiumbicarbonate (20 ml.), 5% potassium bisulfate (15 ml.) and brine (15ml.), dried (anhydrous magnesium sulfate), filtered, evaporated todryness and dried in vacuo. The crude product was chromatographed on asilica gel column (Merck), eluting the column with hexane and ethylacetate:hexane mixtures (1:6; 1:3) to give 3.387 g. of product as asyrup; R_(f) =0.55 (ethyl acetate: hexane, 1:1)

d) (S)-3-Amino-hexahydro-2-oxo-1H-azepine-1-acetic acid, ethyl ester,hydrochloride salt

A solution of the ethyl ester product from part (c) (3,278 g., 10.13mmoles) in dry dioxane (80 ml.) was treated with 4.0M hydrochloricacid/dioxane (31 ml., 0.124 mole, 12 eq.) and stirred at roomtemperature under argon for 20 hours. The reaction mixture was strippedto dryness, evaporating the product several times from ether, then driedin vacuo to give 2.541 g. of product as a white crystalline hygroscopicsolid; R_(f) =0.32 (methylene chloride:methanol:acetic acid, 8:1:1).

e) (S,S)-3- 2-(Acetylthio)methyl!-1-oxo-3-phenylpropyl!amino!-2-oxo-1H-azepine-1-aceticacid, ethyl ester

(S)-2- (Acetylthio)methyl!benzenepropanoic acid, ephedrine salt (1.625g., 4.028 mmoles, 1.01 eq.) was suspended in ethyl acetate (75 ml.),washed with dilute hydrochloric acid (75 ml. water+5.7 ml. 1.0Nhydrochloric acid then 40 ml. water+1.9 ml. 1.0N hydrochloric acid),brine (15 ml.), dried (anhydrous sodium sulfate), filtered andevaporated to dryness. The colorless syrup was dried in vacuo for 1.0hour to afford 1.05 g. of the free acid.

This free acid was dissolved in dry dimethylformamide (25 ml.), cooleddown to 0° (ice-salt bath), treated with 1-hydroxybenztriazole hydrate(567 mg.,4.20 mmoles) and 1-ethyl-3-(3-dimethylaminopropylcarbodiimide(832 mg.,4.34 mmoles) and stirred at 0° under argon for 1.0 hour. Theclear solution was treated with a solution of the ethyl esterhydrochloride salt product of part (d) (1.0 g., 3.988 mmoles) in drydimethylformamide (3.0 ml.) and 4-methylmorpholine (0.45 ml., 1.0 eq.)and stirring was continued at 0° for 1.0 hour and at room temperaturefor 2.0 hours. The reaction mixture was diluted with ethyl acetate (100ml.), washed successively with water (15 ml.), 5% potassium bisulfate(2×15 ml.), saturated sodium bicarbonate (15 ml.) and brine (15 ml.),dried (anhydrous sodium sulfate), filtered, evaporated to dryness anddried in vacuo. The crude product was chromatographed on a silica gelcolumn (Merck), eluting the column with ethyl acetate:hexane mixtures(1:4; 1:2) to give 1.618 g., of product as a syrup; R_(f) =0.030 (ethylacetate:hexane, 1:1).

f) (S,S)-Hexahydro-3-2-(mercaptomethyl)-1-oxo-3-phenylpropyl!amino!-2-oxo-1H-azepine-1-aceticacid

A solution of the ethyl ester product from part (e) (1.537, 3.53 mmoles)in methanol (18 ml.) was purged with argon for 30 minutes, cooled downto 0° (ice-salt bath) then treated dropwise with a previously purged(argon, 30 minutes) solution of 1.0N sodium hydroxide (14.2 ml., 4 eq.)maintaining the bubbling of argon throughout the addition and the lengthof the reaction. The reaction mixture was stirred at 0° for 1.0 hour,acidified at 0° with 5% potassium bisulfate (60 ml.) to pH 2.0 thenextracted with ethyl acetate (2×100 ml.). The organic extracts werewashed with brine (25 ml.), dried (anhydrous sodium sulfate), filtered.evaporated to dryness and dried in vacuo. The crude product wasdissolved in methylene chloride (5 ml.) and treated portionwise withhexane (50 ml.), scratching the mixture to form a solid. The supernatantwas decanted and the solids were triturated with more hexane (3×50 ml.)and the solids were evaporated from pentane (4×40 ml.). The resultingproduct was dried m vacuo 12 hours to give 1.261 g., of product as anamorphous solid; R_(f) =0.43 (methylene chloride:methanol:acetic acid,20:1:1); α!_(D) =+20.2° (c=0.61, methanol). 1H-NMR (400MHz, CDCl₃): 1.46(t,3H), 1.81, (m,6H), 2.60(m,2H), 2.87 (m,3H), 3,21 (m,1H), 3.71 (m,1H),4.17(s,2H), 4.68 (m,1H), 7.13-7.27 (m, 5H).

Anal. calc'd. for C₁₈ H₂₄ N₂ O₄ S.0.2C₅ H₁₂.0,45 H₂ O: C,58.96; H,7.11;N,7.24; S,8.28; SH,8.54; Found: C,58.96; H,6.86; N,7.07; S,8.31;SH,8.43.

EXAMPLE 10 (S,S)-Hexahydro-3-(2-mercapto-1-oxo-3-phenylpropyl)amino!-2-oxo-1H-azepine-1-acetic acid

a) (S,S)-3-2-(Acetylthio)-1-oxo-3-phenylpropyl!amino!-2-oxo-1H-azepine-1-aceticacid, ethyl ester

A suspension of (S)-2-(acetylthio)-benzenepropanoic acid,dicyclohexylamine salt (2.81 g., 6.93 mmoles or 1.01 eq.) was suspendedin ethyl acetate (200 ml.), washed with 5% potassium bisulfate (5×30 ml)and brine (40 ml.), dried (anhydrous magnesium sulfate), filtered,evaporated to dryness and dried in vacuo to give 1.737 g. of the freeacid as a clear syrup.

This free acid was dissolved in dry methylene chloride (30 ml.) andcooled down to 0° (ice-salt bath) treated with 1-hydroxybenztriazolehydrate (978 mg., 7.23 mmoles) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.435 mg., 7.49 mmoles)and stirred at 0° for 1.0 hour. The solution was treated with a solutionof (S)-3-amino-hexahydro-2-oxo-1H-azepine-1-acetic acid, ethyl ester,hydrochloride salt (1.58 g., 6.30 mmoles) in dry methylene chloride (10ml) and 4-methylmorpholine (0.77 ml., 7.01 mmoles) and stirring wascontinued at 0° for 1.0 hour and at room temperature for 1.5 hours. Thereaction mixture was diluted with ethyl acetate (170 ml.), washedsuccessively with water (25 ml.), 5% potassium bisulfate (2×25ml.),saturated sodium bicarbonate (25 ml.) and brine (25 ml.), dried(anhydrous magnesium sulfate), filtered, evaporated to dryness and driedin vacuo. The crude product was chromatographed on a silica gel column(Merck), eluting the column with ethyl acetate:hexanes (3:7) to give2.045 g. of product as a syrup. An additional 261 mg. of the isomermixture (1:1 ratio) was obtained from the column; R_(f) =0.45 (ethylacetate:hexane, 1:1).

b) (S,S)-Hexahydro-3-(2-mercapto-1-oxo-3-phenylpropyl)amino!-2-oxo-1H-azepine-1-acetic acid

A solution of the ethyl ester product from part (a) (2.044 g., 4.86mmoles) in methanol (25 ml.) was purged with argon for 30 minutes,cooled down to 0° (ice-salt bath) then treated dropwise with apreviously purged (argon, 30 minutes) solution of 1.0N sodium hydroxide(19.55 ml., 4 eq.) maintaining the bubbling of argon throughout theaddition and the length of the reaction. The reaction mixture wasstirred at 0° for 1.0 hour, acidified at 0° with 5% potassium bisulfate(85 ml.) to pH 2.0 then extracted with ethyl acetate (2×140 ml.). Theorganic extracts were washed with brine (35 ml.), dried (anhydroussodium sulfate), filtered, evaporated to dryness and dried in vacuo Thecrude product was dissolved in methylene chloride (10 ml.) and treatedportionwise with hexane (50 ml.), scratching the mixture to form asolid. The supernatant was decanted and the solids triturated with morehexane (2×50 ml.) and pentane (2×100 ml.), stirring with the first 100ml. of pentane for 4 hours and the next 100 ml. overnight under argon.The product obtained was then dried in vacuo for 12 hours to give 1.618g. of product as an amorphous solid; R_(f) =0.53 (methylenechloride:methanol:acetic acid, 10:1:1); α!_(D) =+8.04° (c=0.56,methanol). 1HNMR (400MHz, CDCl₃): 1.71 (m,6H), 2.02 (d,1H), 3.16 (m,3H),3.61 (m, 1H), 3.70 (m,1H), 4.17 (s,2H), 4.65 (m,1H), 7.18-7.72 (m,5H).

Anal. calc'd. for C₁₇ H₂₂ N₂ O₄ S: C,58.27; H,6.33; N,7.99; S,9.15;SH,9.44; Found: C,58.43; H,6.56; N,7.85; S,8.96; SH,10.27.

EXAMPLE 11 3R- 3α, 6α(S*), 9aβ!!-Octahydro-6-(2-mercapto-1-oxo-3-phenylpropyl)amino!-5-oxothiazolo3,2-a!!azepine-3-carboxylic acid

a) N² -Phthaloyl-L-lysine

A mixture of N⁶ - (1,1-dimethylethoxy)carbonyl!-L-lysine (10.827 g.,43.9 mmol.) and sodium carbonate (4.665 g., 44.0 mmol.) was stirred in170 ml of ethanol:water (1:3) for 2.5 hours. The ethanol was removed byrotary evaporation and the aqueous solution was treated withN-carbethoxy phthalimide (9.66 g, 44.0 mmol). After stirring at roomtemperature for 1.5 hours, the solution was filtered, treated withmethylene chloride (200 ml), and the aqueous layer was acidified with 6Nhydrochloric acid (to pH 2.8). The layers were shaken and separated. Theaqueous layer was extracted again with ethyl acetate and the pooledorganic layers were dried (magnesium sulfate), filtered, and stripped togive a near colorless oil/glass (19.510 g).

The residue was cooled to 0° C., treated with trifluoroacetic acid (150ml.), and the mixture was let stir at room temperature for 3 hours. Thetrifluoroacetic acid was removed by rotary evaporation and the residuewas azeotroped twice with toluene. The crude product was taken up inwater and run on a Dowex AG 50-X2 (100-200 mesh, 300 ml, acidic form)column eluting in succession with 1:1 methanol:water (600 ml.), water(500 ml.), and finally 5:95 pyridine:water (1000 ml.). The desiredfractions were pooled, stripped, taken up in water and lyophilized togive 7.850 g. of product as a white solid; R_(f) =0.57(n-butanol:water:acetic acid:ethyl acetate, 1:1:1:1)

b)2(S),4R!-4-(Methoxycarbonyl)-α-phthalimido-2-thiazolidinepentanoicacid

A slurry of N² -phthaloyl-L-lysine (7.710 g., 27.9 mmol.) in drydimethylformamide (135 ml.) was treated with 4-formyl-1-methylpyridiniumbenzenesulfonate (7.320 g, 26.2 mmol). The resulting dark mixturegradually became homogeneous. After stirring at room temperature for 1hour, the mixture was treated with 1,8-diazobicyclo 5.4.0!undec-7-ene(8.15 ml, 8.30 g, 54.5 mmol.) followed 5 minutes later with L-cysteine,methyl ester, hydrochloride (4.53 g, 26.3 mmol). The dark solution wasstirred for 2.5 hours, then diluted with aqueous hydrochloric acid (pH1.7, 300 ml.) and chloroform (150 ml.). The aqueous layer was adjustedto pH 4.3-4.4 with 0.5N hydrochloric acid and subsequently extractedfive times with chloroform. The pooled chloroform extracts were washedwith water (50 ml.), dried (sodium sulfate), filtered and stripped. Theresidue was taken up in ethyl acetate, filtered through Celite, andconcentrated to give 1.84 g. of crude product as a dark orange-red oil.R_(f) =0.58 major spot (acetic acid:ethyl acetate, 15:85). NMR shows a2:1 ratio of isomers.

c) 3R-(3α,6α)!-Octahydro-6-phthalimido-5-oxothiazolo3,2-a!azepine-3-carboxylic acid, methyl ester

A solution of the product from part (b) (1.84 g., 4.7 mmol) intetrahydrofuran (70 ml.) was treated with2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (1.400 g., 5.67 mmol.)and the mixture was stirred at room temperature for 3 days. Thetetrahydrofuran was removed by rotary evaporation and the residue wastaken up in ethyl acetate and washed in succession with 0.5Nhydrochloric acid (2×), 50% saturated sodium bicarbonate, water, andbrine, then dried (sodium sulfate), filtered, and stripped. Theresulting orange oil was flash chromatographed (Merck silica gel, 40-50%ethyl acetate in hexanes) to give 1.126 g. of product as a 1:1 mixtureof diastereomers; R_(f) =0.22 and 0.20 (40% ethyl acetate in hexane).

d) 3R-(3α,6α,9aβ)!-Octahydro-6-phthalimido-5-oxothiazolo3,2-a!azepine-3-carboxylic acid, methyl ester

A mixture of the methyl ester product from part (c) (1.110 g.) andp-toluenesulfonic acid hydrate (2.33 g) in benzene (20 ml.) was refluxedwith removal of water (Dean-Stark trap) for 2.5 hours. The cooledmixture was diluted with ethyl acetate and washed with 50% saturatedsodium bisulfate, water, and brine, then dried (sodium sulfate),filtered, and stripped. The residue was flash chromatographed (Mercksilica gel, 10-20% ethyl acetate in methylene chloride) to give nearlypure product as an off-white foam. The foam was dissolved in hot ethylacetate/hexanes, cooled and seeded to give fine white needles (845 mg).An additional 50 mg of solid product was obtained from the mother liquorbringing the total amount of pure product to 895 mg; m.p. 154°-155° C.;α!_(D) =-31.8° (c=0.52, chloroform); R_(f) =0.22 (40% ethyl acetate inhexane).

e) 3R-(3α,6α,9aβ)!-6-Amino-octahydro-5-oxothiazolo-3,2-a!azepine-3-carboxylic acid, methyl ester, hydrochloride salt

A slurry of the methyl ester product from part (d) (875 mg., 2.34 mmol.)in absolute ethanol (50 ml.) was treated with hydrazine hydrate (115 μl,118 mg., 2.37 mmol) and the solution was periodically warmed for thefirst two hours to effect solubilization. After stirring at roomtemperature for 3 days, additional hydrazine hydrate (80 μl., 82.6 mg.,1.65 mmol) was added and the mixture was stirred for one more day. Thereaction was stripped to dryness and the white residual solid wasstirred in cold (0° C.) 0.5N hydrochloric acid (60 ml.) for 3.5 hours.The solid was removed by filtration and the filtrate was made basic with1N sodium hydroxide to pH 11-12 and extracted with methylene chloride(3×) and ethyl acetate. The pooled organic extracts were dried (sodiumsulfate), filtered and stripped to yield a near colorless oil (approx.600 mg). The oil was treated with water (10 ml.) and 1.0N hydrochloricacid (3.0 ml.), swirled until no more oil was present and the mixturewas lyophilized to give 674 mg. of product as a light yellow solid;R_(f) =0.64 major spot (n-butanol:water:acetic acid:ethyl acetate,1:1:1:1).

f) 3R- 3α,6α(S*),9aβ!!-Octahydro-62-(acetylthio)-1-oxo-3-phenylpropyl!amino!-5-oxothiazolo3,2-a!alazepine-3-carboxylic acid, methyl ester

The methyl ester, hydrochloride salt product from part (e) (374 mg.,1.33 mmol.) was partitioned between saturated sodium bicarbonate andmethylene chloride. The methylene chloride extract was dried (sodiumsulfate), filtered and stripped to give the free amine as a pale yellowoil (302 mg., 1.16 mmol.). Additionally,(S)-2-(acetylthio)benzenepropanoic acid, dicyclohexylamine salt (648mg., 1.60 mmol) was partitioned between ethyl acetate and 5% potassiumbisulfate. The ethyl acetate layer was washed with water and brine, thendried (sodium sulfate), filtered and stripped to give the free acid as acolorless oil. A mixture of the free amine and the free acid inmethylene chloride (9 ml.) was treated with hydroxybenztriazole hydrate(550 mg., 4.07 mmol.), cooled to 0° C., and subsequently treated with1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide (313 mg, 1.63 mmol.). Themixture was stirred at 0° C. for 1 hour, then at room temperature for 3hours. Additional 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (100 mg)was added and stirring continued overnight. The solution was dilutedwith ethyl acetate and washed successively with water, 5% potassiumbisulfate, water, 50% saturated sodium bicarbonate, and brine, thendried (sodium sulfate), filtered and stripped. The resulting yellow oilwas flashed chromatographed (Merck silica gel, 30% acetone in hexane) togive 396 mg. of product as a 87:13 mixture of side chain diastereomers.This mixture was again flash chromatographed (Merck silica gel, 35-40%ethyl acetate in hexane) to afford 318 mg., of product as a white foam(94-95% diastereomerically pure); R_(f) =0.29 major and 0.26 minor,6α(R*) isomer!; α!_(D) =-84.4° (c=0.36, chloroform).

g) 3R- 3α,6α(S*),9aβ!!-Octahydro-6-(2-mercapto-1-oxo-3-phenylpropyl)amino!-5-oxothiazolo3,2-a!azepine-3-carboxylic acid

A solution of the methyl ester product from part (f) (308 mg., 0.68mmol.) in methanol (4 ml., deoxygenated via argon bubbling) was treatedwith 1N sodium hydroxide (3.5 ml., deoxygenated via argon bubbling) andthe homogeneous mixture was stirred under argon for 2 hours. The mixturewas acidified with 10% potassium bisulfate (15 ml.), diluted with water,and extracted with ethyl acetate. The ethyl acetate extract was washedwith brine, dried (sodium sulfate), filtered, and stripped to give asolid. The solid was dissolved in dimethylformamide (1 ml.), dilutedwith ethyl acetate, and flash chromatographed (Merck silica gel, 5%acetic acid in ethyl acetate) to give the desired product as a whitesolid which was triturated with ethyl acetate/ethyl ether, collected byfiltration, and dried to give 144 mg., of product; m.p. 217°-220° C.;R_(f) =0.52 (5% acetic acid in ethyl acetate); α!_(D) =-64.3° (c=0.36,dimethylformamide). NMR analysis indicated the product was 93%diasteromerically pure with 7% of the corresponding 6α(R*) isomer.

HPLC: YMC S3 ODS column (6.0×150 mm); eluted with 44% A: 90% water-10%methanol-0.2% phosporic acid and 56% B: 10% water-90% methanol-0.2%phosporic acid; flow rate 1.5 ml/min detecting at 220 nm; t_(R) =12.27min indicates a purity of >95% (no separation of 6α(S*) and 6α(R*)isomers dectected by HPLC)

Anal. calc'd. C₁₈ H₂₂ N₂ O₄ S₂.0.4 H₂ O: C,53.82; H,5.72; N,6.97;S,15.96; SH,8.21; Found: C,53.88; H,5.67; N,6.78; S,15.37; SH,4.91.

EXAMPLE 12 3R- 3α,6α(S*)-9aβ!!-Octahydro-6-2-(mercaptomethyl)-1-oxo-3-phenylpropyl!amino!-5-oxo-thiazolo3,2-a!azepine-3-carboxylic acid

a) 3R- 3α,6α(S*),9aβ!!-Oxahydro-6- 2-(acetylthio)methyl!-1-oxo-3-phenylpropyl!amino!-5-oxothiazolo3,2-a!azepine-3-carboxylic acid, ethyl ester

(S)-2- (Acetylthio)methyl!benzenepropanoic acid, ephedrine salt (481mg., 1.20 mmol.) was partitioned between ethyl acetate and watercontaining 2.0 ml. 1N hydrochloric acid. The ethyl acetate layer waswashed with water and brine, then dried (sodium sulfate), filtered, andstripped to give the free acid as a colorless oil. This free acid wasdissolved in methylene chloride (7 ml.) and treated with3R-(3α,6α,9aβ)!-6-amino-octahydro-5-oxothiazolo3,2-a!azepine-3-carboxylic acid, ethyl ester, hydrochloride salt (293mg., 1.04 mmol.) followed in succession by 4-methyl morpholine (154 μl.,142 mg, 1.4 mmol), dimethylformamide (2.5 ml.), 1-hydroxybenztriazolehydrate (147 mg, 1.08 mmol), and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (226 mg, 1.18 mmol). Afterstirring at room temperature for 2 hours, the mixture was diluted withethyl acetate and washed successively with water, 0.5N hydrochloricacid, water, 50% saturated sodium bicarbonate, and brine, then dried(sodium sulfate), filtered, and stripped. The residue was flashchromatographed (Merck silica gel, 30% acetone in hexanes) to give 357mg. of product as a white foam. R_(f) =0.44 (acetone:hexanes, 1:1);α!_(D) =-77.2° (c=0.50, chloroform). NMR analysis indicated the productwas homogeneous.

b) 3R- 3α,6α(S*),9aβ!!-Octahydro-6-2-(mercaptomethyl)-1-oxo-3-phenylpropyl!amino!-5-oxothiazolo3,2-a!azepine-3-carboxylic acid

The ethyl ester product from part (a) (343 mg., 0.74 mmol.) in methanol(2 ml.,deoxygenated via argon bubbling) was treated with 1N sodiumhydroxide (3.5 ml., deoxygenated via argon bubbling) and the resultingmixture was stirred under argon for 1.5 hours. The solution wasacidified with 5% potassium bisulfate (20 ml.), diluted with water andextracted with ethyl acetate. The ethyl acetate extract was washed withwater and brine, then dried (sodium sulfate), filtered and stripped toafford a white solid. The solid was dissolved in hot methanol/ethylacetate, filtered again, and concentrated to precipitate the desiredproduct. The solid was collected by filtration, washed with ethylacetate and ethyl ether, and dried in vacuo at 50° C for 2 hours to give221 mg. of product as a white solid. An additional 20 mg. of product wasobtained from the mother liquor; m. p. 212°-213° C.; R_(f) =0.55 (5%acetic acid in ethyl acetate); α!_(D) =-36.5° (c=0.36,dimethylformamide).

HPLC: YMC S3 ODS column (6.0×150 mm); eluted with 44% A: 90% water-10%methanol-0.2% phosphoric acid and 56% B: 10% water-90% methanol-0.2%phosphoric acid flow rate at 1.5 ml./min detecting at 220 nm; tR=15.96indicates a purity of 99.2%.

Anal. calc'd. for C₁₉ H₂₄ N₂ O₄ S₂ : C,55.86; H,5.92; N,6.86; S,15.70;SH,8.09; Found: C,55.99; H,6.01; N,6.75; S,15.70; SH,7.81.

EXAMPLE 13 S-(R*,R*)-3,4-Dihydro-3-2-(mercaptomethyl)-1-oxo-3-phenylpropyl!amino!-4-oxo-1,5-benzoxazepine-5(2H)-aceticacid

a) N- (1,1-Dimethylethoxy)carbonyl!-O-(2-nitrophenyl)-L-serine

A solution of N- (1,1-dimethylethoxy)carbonyl!-L-serine (24.3 g., 0.118mole) in dry dimethylformamide (25 ml.) was added dropwise over a periodof 1.0 hour to a cooled (0°, ice-salt bath) suspension of 60% sodiumhydride (10.1 g., 0.25 mole) in dry dimethylformamide (200 ml.) andstirring was continued at 0° until the frothing subsided (about 2.0hours). The reaction mixture was treated dropwise with1-fluoro-2-nitrobenzene (14.3 ml., 0.13 mole) over a period of 20minutes, stirred at 0° under argon for 4.0 hours then poured intoice-water (750 ml.) and extracted with ethyl acetate (2×100 ml.). Theaqueous phase was brought to pH 1.0 with 6 N hydrochloric acid (70 ml.),extracted with ethyl acetate (3×500 ml.) and the combined organicextracts were washed with brine (100 ml.), dried (anhydrous sodiumsulfate), filtered, evaporated to dryness and dried in vacuo. The crudeproduct mixture was chromatographed on a silica gel column (Merck),eluting the column with methylene chloride:methanol:acetic acid(100:5:0.2) to give 27.22 g. of product as a thick yellow syrup; R_(f)=0.27 (methylene chloride:methanol:acetic acid, 100:5:0.5).

b) N- (1,1-Dimethylethoxy)carbonyl!-O-(2-aminophenyl)-L-serine

A solution of the product from part (a) (27.1 g., 83 mmoles) in drymethanol (500 ml.) was treated with 10% palladium on carbon catalyst(900 mg.) and hydrogenated at 40 psi for 2.0 hours. The reaction mixturewas filtered through a celite pad in a millipore unit, washing the padwell with methanol (5×100 ml.). The dark filtrate was evaporated todryness and dried in vacuo to give a dark solid. The crude product wastriturated with methylene chloride:hexane (1:4) to give 17.69 g. ofproduct as a light tan solid; R_(f) =0.15 (methylenechloride:methanol:acetic acid, 20:1:1).

c) (S)-3-(Dimethylethoxy)carbonyl!amino!-2,3-dihydro-1,5-benzoxazepin-4(5H)-one

A solution of the product from part (b) (16.69 g., 56.3 mmoles) in drydimethyformamide (121 ml.) was treated with1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide (10.64 g., 55.5 mmoles)and stirred at room temperature for 3.0 hours. The reaction mixture waspartitioned between ethyl acetate (2×492 ml.) and 1.0N sodiumbicarbonate (492 ml.), and the combined organic extracts were washedwith water (3×492 ml.), brine (492 ml.), dried (anhydrous magnesiumsulfate), filtered, evaporated to dryness and dried in vacuo. The crudeproduct was chromatographed on a silica gel column (Merck), eluting thecolumn with ethyl acetate:hexane mixtures (1:4; 1:2; 1:1) to give 10.5g. of product as off-white crystals; R_(f) =0.40 (ethyl acetate:hexane,1:4).

d) (S)-3-(Dimethylethoxy)carbonyl!amino!-3,4-dihydro-4-oxo-1,5-benzoxazepine-5(2H)-aceticacid, ethyl ester

A solution of the product from part (c) (1.0 g., 3.59 mmoles) in drytetrahydrofuran (10 ml.) was cooled down to 0° (ice-salt bath) underargon, treated with powdered potassium hydroxide (259 mg., 4.6 mmoles)and tetrabutylammonium bromide (172 mg., 0.53 mmole), stirred for 5minutes then treated with ethyl 2-bromoacetate (0.50 ml., 1.2 eq.). Thereaction mixture was stirred at room temperature under argon for 19.0hours, partitioned between methylene chloride (2×25 ml.) and water (13ml.) and the combined organic extracts were washed with water (2×13ml.), brine (10 ml.), dried (anhydrous sodium sulfate), filtered,evaporated to dryness and dried in vacuo. The crude product mixture waschromatographed on a silica gel (Merck), eluting the column with ethylacetate:hexane mixtures (1:9; 1:4) to give 860 mg. as a syrup; R_(f)=0.67 (ethyl acetate:hexanes, 1:1).

e) (S)-3-Amino-3,4-dihydro-4-oxo-1,5-benzoxazepine-5(2H)-acetic acid,ethyl ester, hydrochloride salt

A solution of the product from part (d) (4.0 g., 11 mmoles) in drydioxane (85 ml.) was treated with 4.0M hydrochloric acid/dioxane (33.6ml., 0.134 mole or 12.2 eq.) and stirred at room temperature for 20hours. The reaction mixture was evaporated to dryness, evaporating theresulting syrup from toluene (2×) and ethanol (1×) then dried in vacuoto give 3.466 g. of product as a light gold-colored syrup; R_(f) =0.48(methylene chloride:methanol, 9:1).

f) S,(R*,R*)!-3- 2-(Acetylthio)methyl!-1-oxo-3-phenylpropyl!amino!-3,4-dihydro-4-oxo-1,5-benzoxazepine-5(2H)-aceticacid, ethyl ester

(S)-2- (Acetylthio)methyl!benzenepropanoic acid, ephedrine salt (1.547g., 3.83 mmoles, 1.01 eq.) was suspended in ethyl acetate (70 ml.),washed with dilute hydrochloric acid (70 ml. water+5.4 ml. 1.0Nhydrochloric acid then 35 ml. water+1.8 ml. 1.0N hydrochloric acid),brine (15 ml.), dried (anhydrous magnesium sulfate), filtered andevaporated to dryness. The colorless syrup was dried in vacuo for 1.0hour to afford 1.02 g. of the free acid.

This free acid was dissolved in dry dimethylformamide (22 ml.), cooleddown to 0° (ice-salt bath), treated with 1-hydroxybenztriazole hydrate(541 mg., 3.99 mmoles) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(792.5 mg., 4.13 mmoles) and stirred at 0° under argon for 1.0 hour. Theclear solution was treated with the product from part (e) (1.147 g.,3.81 mmoles) followed by 4-methylmorpholine (0.47 ml., 4.23 mmoles) andstirring was continued at 0° for 1.0 hour and at room temperature for1.0 hour. The reaction mixture was diluted with ethyl acetate (92 ml.),washed successively with water (14 ml.), 5% potassium bisulfate (2×14ml.), water (14 ml.), saturated sodium bicarbonate (14 ml.) and brine(14 ml.), dried (anhydrous sodium sulfate), filtered, evaporated todryness and dried in vacuo. The crude product was chromatographed on asilica gel column (Merck), eluting the column with ethyl acetate:hexane(1:4) to give 1.516 g. of the product as a white syrupy foam; R_(f)=0.62 (ethyl acetate:hexanes, 1:1).

g) S-(R*,R*)!-3,4-Dihydro-3-2-(mercaptomethyl)-1-oxo-3-phenylpropyl!amino!-4-oxo-1,5-benzazepine-5(2H)-aceticacid

A solution of the ethyl ester product from part (f) (1.481 g., 3.056mmoles) in methanol (15.5 ml.) was purged with argon for 30 minutes,cooled down to 0° (ice-salt bath) then treated dropwise with apreviously purged (argon, 30 minutes) solution of 1.0N sodium hydroxide(12.2 ml., 4.0 eq.) maintaining the bubbling of argon throughout theaddition and the length of the reaction. The reaction mixture wasstirred at 0° for 1.0 hour, acidified at 0° with 5% potassium bisulfate(53 ml.) to pH 1.0 then extracted with ethyl acetate (2×100 ml.). Theorganic extracts were washed with brine (25 ml.), dried (anydrous sodiumsulfate), filtered, evaporated to dryness and dried in vacuo. The crudeproduct was dissolved in methylene chloride (10 ml.) and treatedportionwise with hexane (100 ml.), scratching the mixture to form asolid. The supernatant was decanted and the solids triturated with morehexane (50 ml.) and pentane (2×100 ml.), stirring with the first 100 ml.of pentane for 4.0 hours and the next 100 ml. overnight under argon. Theproduct obtained was then dried in vacuo for 6.0 hours to give 1.273 g.of product as an amorphous solid; R_(f) =0.62 (methylenechloride:methanol:acetic acid, 20:1:1:1); α!_(D) =-140.2° (c=0.61,methanol).

1H NMR (400 MHz, CDCl₃): 1.43 (t,1H), 2.51-2.90 (m, 5H), 4.17, (t,1H,J=10 Hz), 4.29 (d,1H, J=17 Hz), 4.69 (t, 1H, J=7 Hz), 4.71 (d, 1H, J=17Hz), 6.76 (d,1H), 7.05-7.26 (m,9H).

Anal. calc'd. for C₂₁ H₂₂ N₂ O₅ S: C,60.86; H,5.35; N,6.76; S,7.74;SH,7.98; Found: C,60.85; H,5.54; N,6.74; S,7.66; SH,6.29.

EXAMPLE 14 S,(R*,R*)!-3,4-Dihydro-3-(2-mercapto-1-oxo-3-phenylpropyl)amino!-4-oxo-1,5-benzoxazepine-5(2H)-aceticacid

a) S,(R*R*)-3-2-(Acetylthio)-1-oxo-3-phenylpropyl!amino!-3,4-dihydro-4-oxo-1,5-benzoxazeiine-5(2H)-aceticacid, ethyl ester

(S)-2-(Acetylthio)benzenepropanoic acid, dicyclohexylamine salt (1.35g., 3.81 mmoles) was suspended in ethyl acetate (120 ml.), washed with5% potassium bisulfate (5×20 ml.) and brine (25 ml.), dried (anhydrousmagnesium sulfate), filtered, evaporated to dryness and dried in vacuoto give the free acid.

This free acid was dissolved in dry methylene chloride (25 ml.), cooleddown to 0° (ice-salt bath), treated with 1-hydroxybenztriazole hydrate(541 mg., 4.0 mmoles) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(792 mg., 4.13 mmoles) and stirred at 0° for 1.0 hour under argon. Thesolution was treated with(S)-3-amino-3,4-dihydro-4-oxo-1,5-benzoxazepine-5(2H)-acetic acid, ethylester (1.147 g., 3.81 mmoles) and 4-methylmorpholine (0.47 ml., 4.2mmoles) and stirring was continued at 0° for 1.0 hour and at roomtemperature for 1.0 hour. The reaction mixture was diluted with ethylacetate (100 ml.), washed successively with water (15 ml.), 5% potassiumbisulfate (2×15 ml.), water (15 ml.), saturated sodium bicarbonate (15ml.) and brine (15 ml.), dried (anhydrous sodium sulfate), filtered,evaporated to dryness and dried in vacuo. The crude product waschromatographed on a silica gel column (Merck), eluting the column withethyl acetate:hexane (1:4) to give 1.21 g. of the product as a syrup. Anadditional 409.6 mg. of product (isomer mixture 1:1 ratio) was alsoobtained; R_(f) =0.67 (ethyl acetate:hexanes, 1:4 then 1:1).

b) S,(R*,R*)!-3,4-dihydro-3-(2-mercapto-1-oxo-3-phenylpropyl)amino!-4-oxo-1,5-benzoxazepine-5(2H)-aceticacid

A solution of the ethyl ester product from part (a) (1.81 g., 2.51mmoles) in methanol (13 ml.) was purged with argon for 30 minutes,cooled down to 0° (ice-salt bath) then treated dropwise with apreviously purged (argon, 30 minutes) solution of 1.0N sodium hydroxide(10 ml., 4.0 eq.) maintaining the bubbling of argon throughout theaddition and length of the reaction. The reaction mixture was stirred at0° for 1.0 hour, acidified at 0° with 5% potassium bisulfate (45 ml.) topH 1.0 and extracted with ethyl acetate (2×80 ml.). The combined organicextracts were washed with brine (20 ml.), dried (anhydrous sodiumsulfate), filtered, evaporated to dryness and dried in vacuo. The crudeproduct was dissolved in methylene chloride (10 ml.) and treatedportionwise with hexane (100 ml.), scratching the mixture to form asolid. The supernatant was decanted and the solids triturated withhexane (50 ml.) and pentane (2×100 ml.), stirring with the first 100 ml.of pentane for 4.0 hours and the next 100 ml. overnight under argon. Theproduct was then dried in vacuo for 6.0 hours to give 969.7 mg. as anamormphous solid; R_(f) =0.47 (methylene chloride:methanol:acetic acid,20:1:1); α!_(D) =-143.3° (c=0.54, methanol). 1H NMR (400 MHz, CDCl₃):2.02 (d,1H), 3.07 (m,2H), 3.59 (m,1H), 4.09 (t, 1H, J=10 Hz), 4.24 (d,1H, J=17 Hz), 4,63 (t, 1H, J=8 Hz), 4.73 (d, 1H, J=17 Hz), 4.93 (m, 1H,)7.04-7.26 (m, 9H), 7.42 (d, 1H).

Anal. calc'd. for C₂₀ H₂₀ N₂ O₅ S.0.147 C₅ H₁₂.0.43 H₂ O: C,59.46;H,5.44; N,6.69; S,7.65; SH,7.89; Found: C,59.46; H,5.25; N,6.65; S,7.88;SH,7.84

EXAMPLE 15 3S- 2(R*),3α(R*)!-3-(2-Mercapto-1-oxo-3-phenylpropyl)amino!-α-methyl-2-oxohexahydro-1H-azepine-1-aceticacid

a) 3S- 1(R*),3α(R*)!!-3-2-(acetylthio)-1-oxo-3-phenylpropyl!amino!-.alpha.-methyl-2-oxohexahydro-1H-azepine-1-aceticacid, methyl ester

A cold (0°) solution ofS-(R*,R*)!-3-aminohexahydro-α-methyl-2-oxo-1H-azepine-1-acetic acid,methyl ester (374 mg., 1.75 mmol) prepared as described by Thorsett etal., "Peptides:Structure and Function", Proceeding 8th American PeptideSymposium, p 555 (1983)! and (S)-2-(acetylthio)benzenepropanoic acid(393 mg., 1.75 mmol) in methylene chloride (10 ml.) was treated withtriethylamine (245 μl, 178 mg., 1.76 mmol) followed bybenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluoro-phosphate(775 mg, 1.75 mmol). The clear, nearly colorless solution was stirred at0° C. for one hour and then at room temperature for 3 hours. The mixturewas partitioned between ethyl acetate and 0.5N hydrochloric acid and theethyl acetate extract was washed successively with water, half saturatedsodium bicarbonate and brine. The solution was dried (sodium sulfate),filtered and stripped. The residue was flash chromatographed (Mercksilica gel, 70:30 ethyl acetate:hexanes) to give 590 mg. of pure productas a colorless oil/foam; R_(f) =0.43 (ethyl acetate:hexanes, 75:25).

b) 3S- 1(R*),3α(R*)!!-3-(2-Mercapto-1-oxo-3-phenylpropyl)amino!-.alpha.-methyl-2-oxohexahydro-1H-azepine-1-aceticacid

An ice cold solution of the product from part (a) (570 mg., 1.36 mmol)in methanol (7 ml., deoxygenated via argon bubbling) was treated with 1Nsodium hydroxide (5.5 ml., deoxygenated via argon bubbling). Afterstirring at 0° C. for 1.25 hours, the solution was acidified with 1Nhydrochloric acid (9 ml) and extracted with ethyl acetate. The ethylacetate extract was washed with water and brine, then dried (sodiumsulfate), filtered and stripped to afford an oil. The material was flashchromatographed (Merck silica gel, 2% acetic acid in ethyl acetate). Theproduct containing fractions were pooled and stripped, and the residuewas taken up in ethyl acetate and washed successively with water andbrine, then dried (sodium sulfate), filtered and stripped again. Theresulting oil/foam was triturated first with ethyl ether and then withhexane to produce a white oil/foam. The mixture was stripped to dryness,slurried in hexane, stripped to dryness again, and dried in vacuo togive 470 mg. of product as a white foam; (>98% diastereomeric purity asdetermined by NMR analysis); R_(f) =0.49 (5% acetic acid in ethylacetate); α!_(D) =-37.1° (c=0.6, chloroform). HPLC: YMC S3 ODS column(6.0×150 mm); eluted with 44% A: 90% water-10% methanol-0.2% phosphoricacid and 56% B: 10% water-90% methanol-0.2% phosphoric acid; flow rate1.5 ml/min detecting at 220 nm; t_(R) =11.02 min (98.0%).

Anal. calc'd. for C₂₁ H₂₂ N₂ O₄ S₂ : C,59.32; H,6.64; N,7.69; S,8.80;SH,9.07; Found C,59.27; H,6.92; N,7.37; S,8.36; SH,8.75.

EXAMPLE 16 6R(S*)-2,3,6,7-Tetrahydro-6-2-(mercaptomethyl)-1-oxo-3-phenylpropyl!amino!-5-oxo-1,4-thiazepine-4(5H)-aceticacid

a) 2- (Methylsulfonyl)oxy!ethyl!carbamic acid, 1,1-dimethylethyl ester

Di-tert-butyldicarbonate (21.8 g., 100 mmol) was added in portions to astirred solution of ethanolamine (6.1 g., 100 mmol) in dichloromethane(100 ml.) at 0°-5° C. After addition was complete, the cooling bath wasremoved and the solution was stirred at room temperature for five hours.The solvent was removed in vacuo and the resulting material wasdissolved in dichloromethane (100 ml.) and triethylamine (21 ml., 150mmol), cooled to -10° C. and treated dropwise, over a period of 10minutes, with methanesulfonyl chloride (9.25 g., 150 mmol). The mixturewas diluted with ethyl acetate (200 ml.) and washed with 1N hydrochloricacid and water. The ethyl acetate layer was dried (magnesium sulfate),filtered, and freed of solvent in vacuo to give the product as a viscousoil which was used without purification.

b) S- 2- (1,1-Dimethylethoxy)carbonyl!amino!ethyl!-N-(phenylmethoxy)carbonyl!-L-cysteine, diihenylmethyl ester

A solution of N- (phenylmethoxy)carbonyl!-L-cysteine, diphenylmethylester (12.7 g., 30.1 mmol.) and the product from part (a) (7.20 g., 30.1mmol) in dimethylformamide (190 ml.) was treated with spray driedpotassium fluoride (25 g., 430 mmol) and stirred at 70°-75° C., under anatmosphere of argon, for 20 hours. After cooling, the mixture waspartitioned between ethyl acetate (800 ml.) and water (400 ml.). Theorganic layer was washed with brine (300 ml.), dried (magnesiumsulfate), filtered, and freed of solvent in vacuo leaving an oil. Thiswas chromatographed on silica gel (Merck, ˜1000 ml.), eluting withmixtures of ethyl acetate and hexane (1:4, 1:3 and 1:2), to give 9.13 g.of product; R_(f) =0.35, (ethyl acetate:hexanes, 1:2).

c) (R)-Tetrahydro-6-(phenylmethoxy)carbonyl!-amino!-1,4-thiazepin-5(4H)-one

A solution of the product from part (b) (6.13 g., 10.86 mmol) in anisole(30 ml.) and trifluoroacetic acid (45 ml.) was stirred at roomtemperature for two hours and then concentrated in vacuo. The residualoil was diluted with isopropyl ether (40 ml.), stirred, and theisopropyl ether layer was decanted. This process was repeated once moreand the residue was dried in vacuo. A mixture this material anddiphenylphosphoryl azide (4.4 g., 16 mmol) in dry dimethylformamide (75ml.) under an argon atmosphere was cooled in an ice bath and, whilestirring, 4-methylmorpholine (4.45, 44 mmol) was added dropwise. Afteraddition was complete, the mixture was allowed to warm to roomtemperature and left stirring for 20 hours. The mixture was partitionedbetween ethyl acetate (150 ml. and water (100 ml.). The layers wereseparated and the aqueous layer was reextracted with ethyl acetate (50ml.). The combined organic layers were washed with saturated potassiumbisulfate solution (30 ml.), saturated sodium bicarbonate solution (50ml.), and brine (50 ml.), dried (magnesium sulfate), and freed ofsolvent in vacuo. The remaining material was triturated with isopropylether to give 2.45 g. of white solid product. R_(f) =0.27, (ethylacetate:hexanes, 1:1).

d) (R)-Tetrahydro-5-oxo-6-(phenylmethoxy)-carbonyl!amino!-1,4-thiazepine-4(5H)-acetic acid, ethylester

A solution of the product from part (c) (3.55 g., 12.68 mmol) indistilled tetrahydrofuran (40 ml.), under an atmosphere of argon, wascooled to 0° C. and treated with powdered potassium hydroxide (2.16 g.,40 mmol) and tetrabutylammonium bromide (420 mg., 1.3 mmol). Ethylbromoacetate (2.58 g., 15.43 mmol) was added dropwise. The mixture wasstirred cold for two hours and then diluted with ethyl acetate (50 ml.),and anhydrous magnesium sulfate was added. The reaction mixture wasfiltered through a magnesium sulfate pad and the pad was washed severaltimes with ethyl acetate. The filtrate was treated with lN hydrochloricacid solution (50 ml.) and the layers were separated. The organic layerwas dried (magnesium sulfate), filtered and freed of solvent in vacuoleaving an oil which was purified by chromatography on silica gel,eluting with 10-30% ethyl acetate in hexane to give 3.22 g. of productas a viscous oil; R_(f) =0.60 (ethyl acetate:hexanes, 1:1).

e) (R)-6-Aminotetrahydro-5-oxo-1,4-thiazepine-4(5H)-acetic acid, ethylester, hydrobromide salt

The product from part (d) (3.17 g., 8.65 mmol) was treated with 30%hydrogen bromide in acetic acid (14 ml.). The mixture was stirred atroom temperature for one hour and then diethyl ether (200 ml.) wasadded. After stirring at room temperature for one hour, the precipitatedsalt was harvested by filtration and washed several times with ether.The slightly gummy material was dissolved in hot ethanol and the solventwas removed in vacuo. This process was repeated once. piethyl ether wasadded to the remaining material and the hydrobromide salt product (2.52g.) was harvested by filtration as a yellow solid.

f) 6R(S*)!-2,3,6,7-Tetrahydro-6- 2-(acetylthio)methyl!-1-oxo-3-phenylpropyl!amino!-5-oxo-1,4-thiazepine-4(5H)-aceticacid, ethyl ester

A suspension of the ephredine salt of (S)-2-(acetylthio)methyl!benzenepropanoic acid (1.74 g., 4.31 mmole) in ethylacetate was washed twice with 0.1N hydrochloric acid (75 ml., 30 ml.),once with brine (25 ml.), dried (magnesium sulfate), filtered and freedof solvent in vacuo leaving the free acid as an oil. This was dissolvedin dichloromethane (25 ml.) under an atmosphere of argon and cooled to0° C. 1-Hydroxybenzotriazole hydrate (642 mg., 4.75 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (949 mg.,5.0 mmol) wereadded. The mixture was stirred cold one hour before the hydrobromidesalt product of part (e) (1.259 g., 4.03 mmol) was added followed by4-methylmorpholine (530 μl, 4.75 mmol). The mixture was stirred cold onehour and one hour at room temperature, then diluted with dichloromethane(100 ml.). The solution was washed with water (30 ml.), 5% potassiumbisulfate solution (30 ml.), sodium bicarbonate solution (30ml.), andwater (30 ml.). The dichloromethane solution was dried (magnesiumsulfate), filtered and freed of solvent in vacuo. The remaining materialwas chromatographed on silica gel (Merck, 350 ml.), eluting withmixtures of ethyl acetate and hexane (1:3 followed by 1:2, 2:3 and 1:1)to give 991 mg., of product; R_(f) =0.40 (ethyl acetate:hexanes, 1:1).

a) 6R(S*)!-2,3,6,7-Tetrahydro-6-2-(mercaptomethyl)-1-oxo-3-phenylpropyl!amino!-5-oxo-1,4-thiazepine-4(5H)-aceticacid

A solution of the product from part (f) (991 mg., 2.19 mmol) in methanol(18 ml.) was purged with argon for 15 minutes, cooled in an ice-saltbath and, while stirring and continuing the argon purge, treateddropwise with 1N sodium hydroxide solution (8.8 ml.) which had beenpurged with argon for 30 minutes just before use. The mixture wasstirred cold one hour and then acidified to pH 2 with 5% potassiumbisulfate solution. The product was extracted into ethyl acetate (2×50ml., 1×20 ml.). The combined organic extracts were washed with brine,dried (magnesium sulfate), filtered and freed of solvent in vacuoleaving a white solid foam. This was dissolved in warm ethyl acatate,filtered, and freed of solvent in vacuo. The remaining material wasdissolved in dichloromethane and hexane was added. Removal of thesolvent in vacuo gave 836 mg. of product as a white solid foam;m.p.85°-101° C.; R_(f) =0.35 (8% methanol in dichloromethane plus 2drops acetic acid/5 ml.); α!_(D) =-9.5° (C=0.6, methanol). HPLC:R_(T)=13.2 min., 50 % aqueous methanol containing 0.2% phosphoric acid, 1.5ml./min., detected at 220 mm, YMC S-3 (ODS), 6.0×150 mm., 3 micronspherical end capped column. H.I.=>95%.

Anal. calc'd. for C₁₇ H₂₂ N₂ O₄ S₂.0.15 H₂ O.0.15 C₆ H₁₄ : C,60.24;H,5.71; N,6.11; S,13.98; Found: C,60.01; H,5.77; N,5.94; S,13.64.

EXAMPLE 17 6R(S*)!-2,3,6,7-Tetrahydro-6-(2-mercacpto-1-oxo-3-phenylpropyl)amino!-5-oxo-1,4-thiazepine-4(5H)-aceticacid

a) 6R(S*)!-2,3,6,7-Tetrahydro-6-2-(acetylthio)-1-oxo-3-phenylpropyl!amino!-5-oxo-1,4-thiazepine-4(5H)-aceticacid, ethyl ester

A suspension of the dicyclohexylamine salt of(S)-2-(acetylthio)benzenepropanoic acid (1.74 g., 4.29 mmol) in ethylacetate (75 ml.) was washed twice with 0.1N hydrochloric acid (75 ml.,30 ml.), once with brine (30 ml.), dried (magnesium sulfate), filteredand freed of solvent in vacuo leaving the free acid as an oil. This wasdissolved in dichloromethane (25 ml.) under an atmosphere of argon andcooled to 0° C. 1-Hydroxybenzotriazole hydrate (642 mg, 4.75mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (959 mg., 5.0 mmol) wereadded. The mixture was stirred cold one hour before the hydrobromidesalt product of Example 16(e) (1.259 g., 4.03 mmol) was added followedby 4-methylmorpholine (530 μl., 4.75 mmol). The mixture was stirred cold1 hour and 1.5 hours at room temperature, then diluted withdichloromethane (100 ml.). The solution was washed with water (30 ml.),5% potassium bisulfate solution (30 ml.), sodium bicarbonate solution(30 ml.), and water (30 ml.). The dichloromethane solution was dried(magnesium sulfate), filtered and freed of solvent in vacuo. Theremaining foam was chromatographed on silica gel (Merck, 350 ml.),eluting with 30-40 % ethyl acetate in hexane to give 636 mg. of product;R_(f) =0.29 (ethyl acetate:hexane, 1:1).

b) 6R(S*)!-2,3,6,7-Tetrahydro-6-(2-mercapto-1-oxo-3-phenylpropyl)amino!-5-oxo-1,4-thiazepine-4(5H)-aceticacid

A solution of the product from part (a) (636 mg., 1.45 mmol) in methanol(15 ml.) was purged with argon for 15 minutes, cooled in an ice-saltbath and, while stirring and continuing the argon purge, treateddropwise with lN sodium hydroxide solution (5.8 ml.) which had beenpurged with argon for 30 minutes just prior to use. The mixture wasstirred cold one hour and then acidified to pH 1 with 5% potassiumbisulfate solution. The product was extracted into ethyl acetate (2×50ml.). The combined organic extracts were washed with brine, dried(magnesium sulfate), filtered and freed of solvent in vacuo leaving aviscous oil. This was dissolved in dichloromethane and freed of solventin vacuo to give 532 mg. of product as a solid foam; m.p. 69°-76° C.R_(f) =0.29, (8% methanol in dichloromethane plus 2 drops acetic acid/5ml.). HPLC: R_(T) =9.6 min., 50% aqueous methanol containing 0.2%phosphoric acid, 1.5 ml. min., detected at 220 mm, YMC S-3 (ODS),6.0×150 mm, 3 micron spherical end capped column. H.I.=98%. The NMRindicates approximately 0.1M of trapped ethyl acetate.

Anal. calc'd. for C₂₂ H₂₄ N₂ O₄ S₂.0.1 C₄ H₈ O₂ : C,52.21; H,5.56;N,7.43; S,17.00; Found: C,52.27; H,5.54; N,7.35; S,16.98.

EXAMPLE 18 3R- 3α,6α(S*)!!-Tetrahydro-6-(2-mercapto-1-oxo-3-phenylpropyl)amino!-5-oxo-3-phenyl-1,4-thiazepine-4(5H)-aceticacid

a) (3R-cis)-Tetrahydro-5-oxo-3-phenyl-6-(phenylmethoxy)carbonyl!amino!-1,4-thiazepine-4(5H)-acetic acid, ethylester

A solution of (3R-cis)-tetrahydro-3-phenyl-6-(phenylmethoxy)carbonyl!amino!-1,4-thiazepin-5(4H)-one (1.16 g., 3.25mmol) prepared as described by Yanagisawa et al., J. Med. Chem., Vol.30, p. 1984-1991 (1987)! in distilled tetrahydrofuran (30 ml.), under anatmosphere of argon, was cooled to 0° C. and treated with powderedpotassium hydroxide (540 mg., 10 mmol) and tetrabutylammonium bromide(97 mg, 0.3 mmol). Ethyl bromoacetate (501 mg., 3 mmol) was addeddropwise with stirring. The mixture was stirred cold for two hours andthen additional ethyl bromoacetate (501 mg., 3 mmol) was added. Themixture was stirred cold for an additional two hours and then dilutedwith ethyl acetate (50 ml) and anhydrous magnesium sulfate was added.The reaction mixture was filtered through a magnesium sulfate pad andthe pad was washed several times with ethyl acetate. The filtrate waspoured into cold 1N hydrochloric acid solution (40 ml) and the layerswere separated. The organic layer was dried (magnesium sulfate),filtered and freed of solvent in vacuo leaving an oil which was purifiedby chromatography on silica gel, eluting with 10-30% ethyl acetate inhexane to give 730 mg. of product; R_(f) =0.32 (ethyl acetate:hexanes,1:2).

b) (3R-cis)-6-Aminotetrahydro-5-oxo-3-phenyl-1,4-thiazepine-4(5H)-aceticacid, ethyl ester, hydrobromide salt

The product from part (a) (1.43 g., 3.23 mmol) was treated with 30%hydrogen bromide in acetic acid (5.5 ml.). The mixture was stirred atroom temperature for two hours and then diethyl ether (100 ml.) wasadded. After stirring at room temperature for one hour, the precipitatedsalt was harvested by filtration and washed several times with ether togive 1.08 g. of the hydrobromide salt product as a beige solid.

c) 3R- 3α,6α(S*)!!-6-2-(Acetylthio)-1-oxo-3-phenylpropyl!amino!-tetrahydro-5-oxo-3-phenyl-1,4-thiazepine-4(5H)-aceticacid, ethyl ester

A suspension of the dicyclohexylamine salt of(S)-2-(acetylthio)benzenepropanoic acid (736 mg., 1.81 mmol) in ethylacetate (30 ml.) was washed twice with 0.1N hydrochloric acid (40 ml.,20 ml.) and once with brine (20 ml.), dried (magnesium sulfate),filtered, and freed of solvent in vacuo leaving the free acid as an oil.

The hydrobromide salt product from part (b) (640 mg., 1.65 mmol) wasdissolved in dichloromethane (30 ml.), washed with sodium bicarbonatesolution (2×20 ml.), then brine (20 ml.), dried (magnesium sulfate),filtered, and freed of solvent in vacuo leaving the free amine as aviscous oil (495 mg.). This and the free acid above were dissolved indichloromethane (20 ml.) under an atmosphere of argon and cooled to 0°C. 1-Hydroxybenzotriazole hydrate (256 mg., 1.90 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (362.5 mg., 1.90 mmol)were added. The mixture was stirred cold for three hours and thendiluted with dichloromethane (30 ml.). The solution was washed withwater (15 ml.), 5% potassium bisulfate solution (15 ml.), sodiumbicarbonate solution (15 ml.), and water (15 ml.). The dichloromethanesolution was dried (magnesium sulfate), filtered and freed of solvent invacuo. The remaining material was chromatographed on silica gel (Merck,approximately 150 ml.), eluting with 25% ethyl acetate in hexane to give610 mg. of product; R_(f) =0.53 (ethyl acetate:hexanes, 1:1).

d) 3R- 3α,6α(S*)!!-Tetrahydro-6-(2-mercapto-1-oxo-3-phenylpropyl)amino!-5-oxo-3-phenyl-1,4-thiazepine-4(5H)-aceticacid, mixture of methyl and ethyl esters

A solution of the product from part (c) (610 mg., 1.185 mmol) inmethanol (12 ml.) was purged with argon for 15 minutes, cooled in anice-salt bath and, while stirring and continuing the argon purge,treated dropwise with lN sodium hydroxide solution (4.75 ml.) which hadbeen purged with argon for 30 minutes just before use. The mixture wasstirred cold for 75 minutes and then acidified to pH 1 with 5% potassiumbisulfate solution. The product was extracted into ethyl acetate (2×40ml.). The combined organic extracts were washed with brine, dried(magnesium sulfate), filtered and freed of solvent in vacuo leaving 533mg. of product that slowly crystallized. The NMR and mass spectra ofthis material indicated it was a mixture of methyl and ethyl esters.R_(f) =0.76 (5% methanol in methylene chloride plus 2 drops aceticacid/5 ml.)

e) 3R- 3α,6α(S*)!!-Tetrahydro-6-(2-mercapto-1-oxo-3-phenylpropyl)amino!-5-oxo-3-phenyl-1,4-thiazepine-4(5H)-aceticacid

The product from part (d) (480 mg., approximately 1.03 mmol) was addedto methanol (12 ml.). The material crystallized out. Distilledtetrahydrofuran (5 ml.) was added and the mixture became a clearsolution which was purged with argon for 15 minutes, cooled in anice-salt bath and, while stirring and continuing the argon purge,treated dropwise with 1N sodium hydroxide solution (4 ml.) which hadbeen purged with argon for 30 minutes just before use. The mixture waskept cold and under argon for 27 hours. At this time TLC indicated thatthe hydrolysis of the ester was complete. The mixture was acidified topH 1 with 5% potassium bisulfate solution. The product was extractedinto dichloromethane (2×30 ml.). The combined organic extracts werewashed with brine, dried (magnesium sulfate), filtered and freed ofsolvent in vacuo leaving a white solid foam. This was dissolved indichloromethane and hexane was added to turbidity. The mixture was freedof solvent in vacuo leaving a solid. This was triturated with 20% hexanein ether. White solid was harvested by filtration, washed with cold 50%hexane in ether to give 350 mg. of product; m.p.175°-182° C.; R_(f)=0.42 (5% methanol in methylene chloride plus 2 drops acetic acid/5ml.); α!_(D) =+26.7° (c=0.8, methanol). HPLC: R_(T) =8.0 min., 66.8%aqueous methanol containing 0.2% phosphoric acid, 1.5 ml./min., detectedat 220 mm, YMC S-3 (ODS), 6.0×150 mm, 3 micron spherical end cappedcolumn. H.I.=>95%.

Anal. calc'd. for C₂₂ H₂₄ N₂ O₄ S₂ : C,59.44; H,5.44, N,6.30; S,14.42;Found: C,59.52; H,5.54; N,6.08; S,14.14.

EXAMPLE 19 3R- 3α,6α(S*)!!-Tetrahydro-6-2-(mercaptomethyl)-1-oxo-3-phenylpropyl!amino!-5-oxo-3-phenyl-1,4-thiazepine-4(5H)-aceticacid

a) 3R- 3α,6α(S*))!!-Tetrahydro-6- 2-(acetylthio)methyl!-1-oxo-3-phenylpropyl!amino!-5-oxo-3-phenyl-1,4-thiazepine-4(5H)-aceticacid, mixture of methyl and ethyl esters

A suspension of the ephredrine salt of (S)-2-(acetylthio)methyl!benzenepropanoic acid (853 mg., 2.11 mmol.) in ethylacetate (40 ml.) was washed twice with 0.1N hydrochloric acid (40 ml.,20 ml.), once with brine (20 ml.), dried (magnesium sulfate), filtered,and freed of solvent in vacuo leaving the free acid as an oil.

(3R-cis)-6-Aminotetrahydro-5-oxo-3-phenyl-1,4-thiazepine-4(5H)-aceticacid, mixture of methyl and ethyl esters, hydrobromide salt (320 mg. ofethyl ester, 0.82 mmol. and 410 mg. of methyl ester, 1.09 mmol) preparedas described in Example 18(b)! were dissolved in dichloromethane (30ml.), washed with sodium bicarbonate solution (2×20 ml.), brine (20ml.), dried (magnesium sulfate), filtered and freed of solvent in vacuoleaving the free amine as a viscous oil (495 mg., 98%). This and thefree acid described above were dissolved in dichloromethane (20 ml.)under an atmosphere of argon and cooled to 0° C. 1-Hydroxybenzotriazolehydrate (285 mg., 2.11 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (403 mg., 2.11 mmol) wereadded. The mixture was stirred cold 3.5 hours and then diluted withdichloromethane (30 ml.). The solution was washed with water (15 ml.),5% potassium bisulfate solution (15 ml.), sodium bicarbonate solution(15 ml.), and water (15 ml.). The dichloromethane solution was dried(magnesium sulfate), filtered and freed of solvent in vacuo. Theremaining material was chromatographed on silica gel (Merck, 170 ml.),eluting with 25% ethyl acetate in hexane to give 535 mg. of product;R_(f) =0.68 and 0.63, (ethyl acetate:hexanes, 1:1).

b) 3R- 3α,6α(S*)!!-Tetrahydro-6-2-(mercaptomethyl)-1-oxo-3-phenylpropyl!amino!-5-oxo-3-phenyl-1,4-thiazeipine-4(5H)-aceticacid

The product from part (a) (493 mg., approximately 0.98 mmol) wasdissolved in methanol (12 ml.) and purged with argon for 15 minutes,cooled in an ice-salt bath and, while stirring and continuing the argonpurge, treated dropwise with 1N sodium hydroxide solution (4 ml.) whichhad been purged with argon for 30 minutes just before use. The mixturewas kept cold and under argon for 48 hours. At this time TLC indicatedthat the hydrolysis of the ester was complete. The mixture was acidifiedto pH 1 with 5% potassium bisulfate solution. The product was extractedinto dichloromethane (2×30 ml.). The combined organic extracts werewashed with brine (20 ml.), dried (magnesium sulfate), filtered andfreed of solvent in vacuo leaving a white glassy foam. 25% Hexane inether (20 ml.) was added and, on stirring, a white solid formed. Thiswas harvested by filtration and washed with 50% hexane in ether to give342 mg., of product; m.p. 170°-174° C., R_(f) =0.43, (5% methanol inmethylene chloride plus 2 drops acetic acid/5 ml.); α!_(D) =+32.8°(c=0.9, methanol). HPLC: R_(T) =8.6 min., 66.8% aqueous methanolcontaining 0.2% phosphoric acid, 1.5 ml./min., detected at 220 min. YMCS-3 (ODS), 6.0×150 mm, 3 micron spherical end capped column. H.I.=>95%.

Anal. calc'd. for C₂₃ H₂₆ N₂ O₄ S₂ : C,60.24; H,5.71, N,6.11; S,13,98;Found: C,60.25; H,5.77; N,6.06; S,13.85.

EXAMPLE 20 2R- 2α,6β(S*)!!-Tetrahydro-6-2-(mercaptomethyl)-1-oxo-3-phenylpropyl!amino!-5-oxo-2-phenyl-1,4-thiazepine-4(5H)-aceticacid

a) (2R-trans))-Tetrahydro-2-phenyl-6-(phenylmethoxy)carbonyl!amino!-1,4-thiazepin-5(4H)-one

A suspension of (2R-trans)-6-aminotetrahydro-1,4-thiazepin-5(4H)-one(5.82 g.) prepared as described by Yanagisawa et al., J. Med Chem., Vol.30, p. 1984-1991 (1987)! in a mixture of dichloromethane (125 ml.) andtriethylamine (11 ml.) was treated with di-tert-butyl dicarbonate (6 g.)and stirred at room temperature four hours. The mixture was diluted withdichloromethane (100 ml.) and washed with water. The dichloromethanesolution was dried (magnesium sulfate), filtered and freed of solvent invacuo leaving a pale yellow solid. This was chromatographed on silicagel, eluting the product with ethyl acetate:hexane (1:1) followed byethyl acetate to give 2.01 g. of product as a white solid.

b) (2R-trans)-Tetrahydro-5-oxo-2-phenyl-6-(phenylmethoxy)carbonyl!amino!-1,4-thiazepine-4(5H)-acetic acid, methylester

A solution of the product from part (a) (1.95 g., 6.05 mmol) indistilled tetrahydrofuran, under an atmosphere of argon, was cooled to0° C. and treated with powdered potassium hydroxide (1.10 g., 18.15mmol, 3 eq.) and tetrabutylammonium bromide (195 mg.). Ethylbromoacetate (800 μl., 7.26 mmol, 1.2 eq) was added dropwise over aperiod of 30 minutes. The mixture was stirred cold for two hours andthen diluted with dichloromethane (300 ml.) and water (50 ml.). dilutehydrochloric acid solution (75 ml.) was then added and the layers wereseparated. The aqueous layer was reextracted with dichloromethane (100ml.). The combined organic layers were dried (magnesium sulfate),filtered and freed of solvent in vacuo leaving a white foam. The foamwas dissolved in a mixture of ethyl acetate and dichloromethane andtreated with an excess of a solution of diazomethane in ether. Theresulting methyl ester was purified by chromatography on silica gel,eluting with ethyl acetate:hexane (1:1) to give 2.193 g. of product;R_(f) =0.49 (ethyl acetate:hexanes, 1:1).

c)(2R-trans)-6-Aminotetrahydro-5-oxo-2-phenyl-1,4-thiazepine-4(5H)-aceticacid, methyl ester, hydrochloride salt

The product from part (b) (2.19 g., 5.56 mmol) was cooled in an ice bathand treated with a 4N solution of hydrochloric acid in dioxane (15 ml.).The mixture was stirred cold for one hour, during this period a gelformed. The cooling bath was removed and the mixture was stirred at roomtemperature for one hour. The solvent was removed in vacuo and toluenewas added once and removed in vacuo leaving 1.84 g. of product as asolid.

d) 2R- 2α,6β(S*))!!-Tetrahydro-6- 2-(acetylthio)methyl!-1-oxo-3-phenylpropyl!amino!-1-oxo-2-phenyl-1,4-thiazepine-4(5H)-acetic acid, methyl ester

A suspension of the ephredine salt of (S)-2-(acetylthio)methyl!benzenepropanoic acid (1.13 g., 2.80 mmol) in ethylacetate was washed twice with 0.1N hydrochloric acid (50 ml., 25 ml.),once with brine (25 ml.), dried (magnesium sulfate), filtered and freedof solvent in vacuo leaving the free acid as an oil. This was dissolvedin dichloromethane (15 ml.) under an atmosphere of argon and cooled to0° C. 1-Hydroxybenzotriazole hydrate (405 mg., 3.0 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (592 mg., 3.1 mmol) wereadded. The mixture was stirred cold one hour before the hydrochloridesalt product of part (c) (920 mg., 2.79 mmol) was added followed by4-methylmorpholine (306 μl., 2.79 mmol). The mixture was stirred coldone hour and one hour at room temperature, then diluted withdichloromethane (70 ml.). The solution was washed with water (15 ml.),5% potassium bisulfate solution (15 ml.), sodium bicarbonate solution(15 ml.), and water (15 ml.). The dichloromethane solution was dried(magnesium sulfate), filtered and freed of solvent in vacuo. Theremaining material was chromatographed on silica gel (Merck, 170 ml.),eluting with mixtures of ethyl acetate and hexane (1:3 followed by 1:2)to give 1.058 g. of product; R_(f) =0.51 (ethyl acetate:hexanes, 1:1).

e) 2R- 2α,6β(S*)!!-Tetrahydro-6-2-(mercaptomethyl)-1-oxo-3-phenylpropyl!amino!-5-oxo-2-phenyl-1,4-thiazepine-4(5H)-aceticacid

A solution of the product from part (d) (840 mg., 1.63 mmol) in methanol(12 ml.) was purged with argon for 15 minutes, cooled in an ice-saltbath and, while stirring and continuing the argon purge, treateddropwise with 1N sodium hydroxide solution (6.5 ml.) which had beenpurged with argon for 30 minutes just before use. The mixture wasstirred cold for one hour and then acidified to pH 1 with 5% potassiumbisulfate solution. The product was extracted into ethyl acetate (2×40ml.). The combined organic extracts were washed with brine, dried(magnesium sulfate), filtered and freed of solvent in vacuo leaving awhite solid foam. Dichloromethane and ethyl acetate were added and thenremoved in vacuo. Ether was added to the remaining material and a whitesolid was harvested by filtration and washed with additional ether togive 685 mg. of product; m.p.197°-199° C.; R_(f) =0.41 (5% methanol indichloromethane plus 2 drops acetic acid/5 ml.); α!_(D) =+27.1° (c=0.5,methanol).HPLC: R_(T) =10.3 min., 66.8% aqueous methanol containing 0.2%phosphoric acid, 1.5 ml/min., detected at 220 mm, YMC S-3 (ODS), 6.0×150mm, 3 micron spherical end capped column. H.I.=>98%.

Anal. calc'd. for C₂₃ H₂₆ N₂ O₄ S₂ : C,60.24; H,5.71; N,6.11; S,13.98;Found: C,60.01; H,5.77; N,5.94; S,13.64.

EXAMPLE 21 2R- 2α,6β(S*)!!-Tetrahydro-6-(2-mercapto-1-oxo-3-phenylpropyl)amino!-5-oxo-2-phenyl-1,4-thiazepine-4(5H)-aceticacid

a) 2R- 2α,6β(S*)!!-Tetrahydro-6-2-(acetylthio)-1-oxo-3-phenylpropyl!amino!-5-oxo-2-phenyl-1,4-thiazepine-4(5H)-aceticacid, methyl ester

A suspension of the dicyclohexylamine salt of(S)-2-(acetylthio)benzenepropanoic acid (1.13 g., 2.8 mmol) in ethylacetate (50 ml.)was washed twice with 0.1N hydrochloric acid (50 ml., 25ml.), once with brine (25 ml.), dried (magnesium sulfate), filtered andfreed of solvent in vacuo leaving the free acid as an oil. This wasdissolved in dichloromethane (15 ml.) under an atmosphere of argon andcooled to 0° C. 1-Hydroxybenzotriazole hydrate (405 mg., 3.0 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (592 mg, 3.1 mmol) wereadded. The mixture was stirred cold one hour before the aminehydrochloride salt product from Example 20(c) (920 mg., 2.79 mmol, wasadded followed by 4-methylmorpholine (306 μl., 2.79 mmol). The mixturewas stirred cold for one hour and one hour at room temperature, thendiluted with dichloromethane (70 ml.). The solution was washed withwater (15 ml.), 5% potassium bisulfate solution (15 ml.), sodiumbicarbonate solution (15 ml.), and water (15 ml.). The dichloromethanesolution was dried (magnesium sulfate), filtered and freed of solvent invacuo. The remaining material was chromatographed on silica gel (Merck,160 ml.), eluting with mixtures of ethyl acetate and hexane (1:3followed by 1:2) to give 880 mg. of product; R_(f) =0.57 (ethylacetate:hexanes 1:1).

b) 2R- 2α,6β(S*)!!-Tetrtahydro-6-(2-mercapto-1-oxo-3-phenylpropyl)amino!-5-oxo-2-phenyl-1,4-thiazepine-4(5H)-aceticacid

A solution of the product from part (a) (880 mg., 1.75 mmol) in methanol(12 ml.) was purged with argon for 15 minutes, cooled in an ice-saltbath and, while stirring and continuing the argon purge, treateddropwise with 1N sodium hydroxide solution (7.0 ml.) which had beenpurged with argon for 30 minutes just before use. The mixture wasstirred cold for 70 minutes and then acidified to pH 1 with 5% potassiumbisulfate solution. The product was extracted into ethyl acetate (2×40ml.). The combined organic extracts were washed with brine, dried(magnesium sulfate), filtered and freed of solvent in vacuo leaving awhite partially solid material. Ether was added and a white solid washarvested by filtration and washed with additional ether to give 494 mg.of product; m.p.181°-183° C., R_(f) =0.43 (5% methanol indichloromethane+2 drops acetic acid/5 ml.); α!_(D) =+6.7° (c=0.7,methanol). HPLC: R_(T) =9.6 min., 66.8% aqueous methanol containing 0.2%phosphoric acid, 1.5 ml./min., detected at 220 mm, YMC S-3 (ODS),6.0×150 mm, 3 micron spherical end capped column. H.I.=98%. The NMRindicates approximately 0.1M of trapped ethyl acetate.

Anal. calc'd. for C₂₂ H₂₄ N₂ O₄ S₂.0.1 C₄ H₈ O₂ : C,59.34; H,5.51;N,6.18; S,14.14; Found: C,59.22; H,5.41; N,6.12; S,13.72.

EXAMPLE 22 R-(R*,S*)!-2,3,4,5-Tetrahydro-3-(2-mercapto-1-oxo-3-phenylpropyl)amino!-2-oxo-1H-benzazepine-1-aceticacid

a) (R)-2,3,4,5-Tetrahydro-3-amino-2-oxo-1H-benzazepine-1-acetic acid,ethyl ester

2,3,4,5-Tetrahydro-3-amino-2-oxo-1H-benzazepine-1-acetic acid, ethylester prepared as described by Watthey et al., J. Med Chem., 28, p1511-1516 (1985)! (14.8 g., 56.4 mmoles) was resolved via its L-tartaricacid salt by the method described in the aforementioned reference togive the S-amine (3.927 g., m.p. 105°-107°; α!_(D) =-277° (c=0.99,ethanol). The residue from the combined mother liquors (21.5 g., 52.1mmoles) was suspended in ethyl acetate (340 ml.), washed twice with 10 %NH₄ OH (41 ml. then 30 ml.) and brine (25 ml.), dried (anhydrous sodiumsulfate), filtered, evaporated to dryness, and the resulting productdried in vacuo to give the amine mixture (7.01 g.) enriched with the Risomer. A solution of the isomer mixture (2.285 g., 8.71 mmoles) inabsolute ethanol (18 ml.) was treated with D-tartaric acid (1.31 g.,8.73 mmoles) and heated on a steam bath until solution was effected. Theclear solution was cooled down to room temperature, allowed to stand fortwo days then cooled down to 0° (ice-salt bath) and scratched untilcrystals formed. The crude salt (2.585 g.) was recrystallized once fromabsolute ethanol (14 ml.) to give the desired salt 2.158 g., α!_(D)=+154.1°, (c=0.6, methanol)!. The salt was then suspended in ethylacetate (35 ml.), washed with 10% NH₄ OH (2×4 ml.) and brine (6 ml.),dried (anhydrous sodium sulfate), filtered, evaporated to dryness anddried in vacuo to give 1.31 g. of product; R_(f) =0.60 (methylenechloride:methanol, 9:1); α!_(D) =+273.1°, (c=0.677, methanol).

b) R-(R*,S*)!-2,3,4,5-Tetrahydro-3-2-(acetylthio)-1-oxo-3-phenylpropyl!amino!-2-oxo-1H-benzazepine-1-aceticacid, ethyl ester

A suspension of the dicyclohexylamine salt of(S)-2-(acetylthio)benzenepropanoic acid (1.18 g., 2.91 mmoles, 1.1 eq.)in ethyl acetate (84 ml.) was washed with 5% potassium bisulfate (5×13ml.) and brine (18 ml.), dried (anhydrous magnesium sulfate), filtered,evaporated to dryness and dried in vacuo to give the free acid as aclear syrup (720 mg.) in quantitative yield.

The free acid was dissolved in dry methylene chloride (17 ml.), cooleddown to 0° (ice-salt bath) and treated with 1-hydroxybenzotriazolehydrate (412 mg., 3.05 mmoles) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (603.8 mg., 3.15 mmoles).The reaction mixture was stirred at 0° for 1.0 hour under argon, treatedwith the product from part (a) (800 mg., 3.05 mmoles) and stirring wascontinued at 0° for 1.0 hour and at room temperature for 1.0 hour. Thesolution was diluted with ethyl acetate (70 ml.), washed successivelywith water (11 ml.), 5% potassium bisulfate (2×11 ml.), water (11 ml.),saturated sodium bicarbonate (11 ml.) and brine (11 ml.), dried(anhydrous magnesium sulfate), filtered, evaporated to dryness and driedin vacuo. The crude product was chromatographed on a silica gel column(Merck) eluting with ethyl acetate-hexanes (1:4) to give 1.212 g. of theproduct as a syrup; R_(f) =0.57 (ethyl acetate:hexanes, 1:1).

c) R-(R*,S*)!-2,3,4,5-Tetrahydro-3-(2-mercapto-1-oxo-3-phenylpropyl)amino!-2-oxo-1H-benzazeiine-1-aceticacid

A solution of the product from part (b) (1.212 g., 2.59 mmoles) inmethanol (14 ml.) was purged with argon for 30 minutes, cooled down to0° (ice-salt bath) then treated dropwise with a previously purged(argon, 30 minutes) solution of 1.0N sodium hydroxide (13.4 ml., 4.0eq.) maintaining the bubbling of argon throughout the addition andlength of the reaction. The reaction mixture was stirred at 0° for 1.0hour, acidified at 0° with 5% potassium bisulfate (46 ml.) to pH 1.5,warmed up to room temperature then extracted with ethyl acetate (2×90ml.). The organic extracts were washed with brine (22 ml.), dried(anhydrous sodium sulfate), filtered, evaporated to dryness and dried invacuo. The crude product was dissolved in methylene chloride (10 ml.)and treated portionwise with hexane (100 ml.), scratching the mixture toform a solid. The supernatant was decanted and the solids trituratedwith more hexane (50 ml.) and pentane (2×100 ml.), stirring with thefirst 100 ml. of pentane for 4 hours and the next 100 ml. overnightunder argon. The product obtained was then dried in vacuo (pump) for 7hours to give 1.068 g. of product as an amorphous solid; R_(f) =0.67(methylene chloride:methanol:acetic acid, 20:1:1); α!_(D) =+230.90(c=0.57, methanol).

Anal. calc'd. for C₂₁ H₂₂ N₂ O₄ S: C,63.30; H,5.56; N,7.03; S,8.05;SH,8.30; Found: C,63.23; H,5.80; N,6.76; S,7.99; SH,7.67. ¹ H-NMR (400MHz, CDCl₃):δ 1.65 (m, 1H), 2.06 (d, 1H), 2.51 (m, 2H), 2.94 (dd, 1H,J=7, 13 Hz), 3.17 (m, 2H), 3.40 (m, 1H), 4.39 (d, 1H, J=17 Hz), 4.45 (m,1H), 4.67 (d, 1H, J=17 Hz), 7.05-7.31 (m, 9H).

EXAMPLE 23 R-(R*,S*)!-2,3,4,5-Tetrahydro-3-2-(mercaptomethyl)-1-oxo-3-phenylpropyl!amino!-2-oxo-1H-benzazepine-1-aceticacid

a) R-(R*,S*)-2,3,4,5-Tetrahydro-3- 2-(acetylthio)methyl!-1-oxo-3-phenylpropyl!amino!-1H-benzxazepine-1-aceticacid, ethyl ester

The ephedrine salt of (S)-2- (acetylthio)methyl!benzenepropanoic acid(774 mg., 1.92 mmoles, 1.03 eq.) was suspended in ethyl acetate (35ml.), washed with dilute hydrochloric acid (35 ml. water+2.7 ml. 1.0Nhydrochloric acid then 20 ml. water+0.9 ml. 1.0N. hydrochloric acid),and brine (7 ml.), dried (anhydrous magnesium sulfate), filtered andevaporated to dryness. The colorless syrup was dried in vacuo (pump) for1.0 hour to afford a quantitative yield of the free acid (471 mg.).

The free acid was dissolved in dry methylene chloride (15 ml.), cooleddown to 0° (ice-salt bath), treated with 1-hydroxybenzotriazole hydrate(270 mg., 2.0 mmoles) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(396 mg., 2.07 mmoles) and stirred at 0° under argon for 1.0 hour. Theclear solution was treated with the product of Example 22(a) (489 mg.,1.86 mmoles) and stirring was continued at 0° for 1.0 hour and at roomtemperature for 1.0 hour. The reaction mixture was diluted with ethylacetate (50 ml.), washed successively with water (10 ml.), 5% potassiumbisulfate (2×10 ml.), water (10 ml.), saturated sodium bicarbonate (10ml.) and brine (10 ml.), dried (anhydrous magnesium sulfate), filtered,and evaporated to dryness. The crude product was chromatographed on asilica gel column (Merck) eluting the column with ethyl acetate:hexanemixtures (1:4; 1:1) to give 803 mg. of product as a colorless syrup;R_(f) =0.55 (ethyl acetate:hexanes, 1:1).

b) R-(R*,S*)!-2,3,4,5-Tetrahydro-3-2-(mercaptomethyl)-1-oxo-3-phenylpropyl!amino!-2-oxo-1H-benzazepine-1-aceticacid

A solution of the product from part (a) (667 mg., 1.38 mmoles) inmethanol (7 ml.) was purged with argon for 30 minutes, cooled down to 0°(ice-salt bath) then treated dropwise with a previously purged (argon,30 minutes) solution of 1.0N sodium hydroxide (5.5 ml., 4.0 eq.),maintaining the bubbling of argon throughout the addition and length ofthe reaction. The reaction mixture was stirred at 0° for 1.0 hour,acidified at 0° with 5% potassium bisulfate (23 ml.) to pH 2.0, warmedup to room temperature and extracted with ethyl acetate (2×50 ml.). Theorganic extracts were washed with brine (15 ml.), dried (anhydroussodium sulfate), filtered, and evaporated to dryness. The crude productwas dissolved in methylene chloride (5 ml.) and treated portionwise withhexane (50 ml.), scratching the mixture to form a solid. The supernatantwas decanted and the solids were triturated with additional hexane (50ml.) and pentane (2×100 ml.), stirring with the first 100 ml. of pentanefor 4.0 hours and the next 100 ml. overnight under argon. The productobtained was then dried in vacuo (pump) for 9.0 hours to give 486 mg. ofproduct as an amorphous solid; R_(f) =0.53 (methylenechloride:methanol:acetic acid, 20:1:1); α!_(D) =+253.9° (c=0.38,methanol).

Anal. calc'd. for C₂₂ H₂₄ N₂ O₄ S: C,64.06; H,5.86; N,6.79; S,7.77;Found: C,63.83; H,6.08; N,6.40; S,7.75. ¹ H-NMR (400 MHz, CDCl₃):δ 1.51(m, 2H), 2.32-2.52 (m, 4H), 2.77 (m, 3H), 3.17 (m, 1H), 4.36 (d, 1H,J=17 Hz), 4.48 (m, 1H), 4.70 (d, 1H, J=17 Hz), 6.53 (d, 1H), 7.11-7.30(m, 9H).

EXAMPLE 24 S-(R*,S*)!-2,3,4,5-Tetrahydro-3-(2-mercapto-1-oxo-3-phenylpropyl)amino!-2-oxo-1H-1-benzazapine-1-aceticacid

a) (S)-α-Bromobenzenepropanoic acid

A solution of L-phenylalanine (30.0 g., 0.175 mole) and potassiumbromide (73.5 g., 0.618 mole) in 2.5N sulfuric acid (365 ml.) was cooleddown to 0° (ice-salt bath) and treated portionwise with sodium nitrite(19.3 g., 0.28 mole) over a period of 1.0 hour. Stirring was continuedfor 1.0 hour at 0° and at room temperature for 1.0 hour after which thereaction mixture was extracted with ether (3×250 ml.). The combinedorganic extracts were washed with water (100 ml.) and brine (50 ml.),dried (anhydrous magnesium sulfate), filtered, evaporated to dryness anddried in vacuo to give 34.46 g., of product; R_(f) =0.45 (toluene:aceticacid, 95:5).

b) (R)-α-(Acetylthio)benzenepropanoic acid, dicyclohexylamine salt

A suspension of potassium thioacetate (19.25 g., 0.168 mole) in dryacetonitrile (300 ml.) was cooled down to 0° (ice-salt bath) and treateddropwise with a solution of the product from part (a) (34.462 g., 0.15mole) in dry acetonitrile (35 ml.) over a period of 15 minutes. Thereaction mixture was warmed up to room temperature, stirred for 5.0hours under argon then filtered, washing the solids thoroughly withacetonitrile (125 ml.). The clear filtrate was evaporated to dryness anddried in vacuo. The free acid (39.717 g., orange syrup) was dissolved inether (400 ml.), treated with dicyclohexylamine (30.2 ml.,1.0 eq.) andstirred for 30 minutes at room temperature under argon. The whiteprecipitates were filtered off, washed thoroughly with ethyl ether(2×100 ml.) and dried in vacuo overnight at room temperature to give41.0 g. of product; α!_(D) =+31.80 (c=1.4, methanol).

c) S-(R*,S*)!-2,3,4,5-Tetrahydro-3-2-(acetylthio)-1-oxo-3-phenylpropyl!amino!-2-oxo-1H-1-benzazepine-1-aceticacid, ethyl ester

A suspension of the dicyclohexylamine salt of(R)-α-(acetylthio)benzenepropanoic acid (850 mg., 2.1 mmoles) in ethylacetate (60 ml.) was washed with 5% potassium bisulfate (5×10 ml.) andbrine (10 ml.), dried (anhydrous magnesium sulfate), filtered,evaporated to dryness and dried in vacuo to give the free acid as aclear syrup (497 mg.) in quantitative yield.

The free acid was dissolved in dry methylene chloride (12 ml.), cooleddown to 0° (ice-salt bath) and treated with 1-hydroxybenzotriazolehydrate (297 mg., 2.20 mmoles) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (435 mg., 2.27 mmoles).The reaction mixture was stirred at 0° under argon for 1.0 hour, treatedwith (S)-2,3,4,5-tetrahydro-3-amino-2-oxo-1H-benzazepine-1-acetic acid,ethyl ester prepared as described by watthey et al., J. Med. Chem., 28,p 1511-1516 (1985)! (500 mg., 1.91 mmoles) and stirring was continued at0° for 1.0 hour and at room temperature for 1.0 hour. The solution wasdiluted with ethyl acetate (50 ml.) washed successively with water (8.0ml.), 5% potassium bisulfate (2×8 ml.), water (8.0 ml.), saturatedsodium bicarbonate (8.0 ml.) and brine (8.0 ml.), dried (anhydroussodium sulfate), filtered, evaporated to dryness and dried in vacuo. Thecrude product was chromatographed on a silica gel column (Merck),eluting the column with ethyl acetate: hexanes (1:4) to give 714 mg. ofproduct as a clear syrup; R_(f) =0.62 (ethyl acetate:hexanes, 1:1).

d) S-(R*,S*)!-2-3,4,5-Tetrahydro-3-(2-mercapto-1-oxo-3-phenylpropyl)amino!-2-oxo-1H-1-benzazepine-1-aceticacid

A solution of the product from part (c) (714 mg., 1.52 mmoles) inmethanol (9.0 ml.) was purged with argon for 30 mintues, cooled down to0° (ice-salt bath) then treated dropwise with a previously purgedsolution of 1.0N sodium hydroxide (6.0 ml., 4 eq.), maintaining thebubbling of argon throughout the addition and length of the reaction.The reaction mixture was stirred at 0° for 1.0 hour, acidified to pH 2.0with 5% potassium bisulfate (26 ml.) and then extracted with ethylacetate (2×50 ml.). The combined organic extracts were washed with brine(14 ml.), dried (anhydrous sodium sulfate), filtered, evaporated todryness and dried in vacuo. The crude product was dissolved in methylenechloride (5.0 ml.) and treated protionwise with hexane (50 ml.),scratching to form a solid. The supernatant was decanted and the solidstriturated with additional hexane (50 ml.) and pentane (2×100 ml.),stirring with the first 100 ml. of pentane for 4.0 hours and the next100 ml. overnight under argon. The product obtained was then dried invacuo to give the product as an amorphous solid; R_(f) =0.47 (methylenechloride: methanol:acetic acid, 20:1:1); α!_(D) =-228° (c=0.51,methanol).

Anal. calc'd. for C₂₁ H₂₂ N₂ O₄ S.0.26 C₅ H₁₂.0.176 CH₂ Cl2: C,62.46;H,5.94; N,6.48; S,7.42; Found: C,62.81; H,5.87; N,6.53; S,7.29. ¹ H-NMR(400 MHz, CDCl₃): δ 1.65 (m, 1H), 2.06 (d, 1H), 2.51 (m, 2H), 2.95 (dd,1H, J=7, 14 Hz), 3.17 (m, 2H), 4.39 (d, 1H, J=17 Hz), 4.46 (m, 1H), 4.67(d, 1H, J=17 Hz), 7.02-7.31 (m, 9H).

EXAMPLE 25 S-(R*,R*)!-Hexahydro-3-(2-mercapto-1-oxo-3-phenylprolyl)amino!-2-oxo-1(2H)-azocineacetic acid

a) S-(R*,R*)!-Hexahydro-3-(2-acetylthio)-1-oxo-3-phenylpropyl!amino!-2-oxo-1(2H)-azocineaceticacid, 1,1-dimethylethyl ester

A suspension of the dicyclohexylamine salt of(S)-2-(acetylthio)benzenepropanoic acid (2.63 g, 6.6 mmol) in ethylacetate (50 ml.) was washed twice with 0.1N hydrochloric acid (50 ml.,25 ml.) and once with brine (25 ml.), dried (magnesium sulfate),filtered and freed of solvent in vacuo leaving the free acid as an oil.This free acid and (S)-3-aminohexahydro-2-oxo-1(2H)-azocineacetic acid,1,1-dimethylethyl ester prepared according to the procedure of Thorsettet al., J. Med. Chem., 29, 251-60 (1986)! (1.66 g, 6.5 mmol) weredissolved in dichloromethane (30 ml.) under an atmosphere of argon andcooled to 0° C. 1-Hydroxybenzotriazole hydrate (891 mg, 6.6 mmol) and1-ethyl-3-(3-dimethylamino-propyl)carbodiimide (1.26 g., 6.6 mmol) wereadded. The mixture was stirred cold for four hours. The mixture wasdiluted with dichloromethane (100 ml.). The solution was washed withwater (50 ml.), 5% potassium bisulfate solution (50 ml.), sodiumbicarbonate solution (50 ml.), and brine (50 ml.). The dichloromethanesolution was dried (magnesium sulfate), filtered and freed of solvent invacuo. The remaining foam was chromatographed on silica gel (Merck, 500ml.), eluting with 25-50% ethyl acetate in hexane to give 2.252 g. ofproduct; R_(f) =0.35, (ethyl acetate:hexane, 1:1).

b) S-(R*,R*)!-Hexahydro-3-(2-acetylthio)-1-oxo-3-phenylpropyl!amino!-2-oxo-1(2H)-azocineaceticacid

The product from part (a) was dissolved in trifluoroacetic acid (20 ml.and stirred at room temperature for 1.75 hours, under an argonatmosphere. The trifluoroacetic acid was removed in vacuo and toluenewas added twice and removed in vacuo to leave the acid product as awhite foam.

c) S-(R*,R*)!-Hexahydro-3-(2-mercapto-1-oxo-3-phenylpropyl!amino!-2-oxo-1(2H)-azocineacetic acid

A solution of the product from part (b) (5.45 mmol) in methanol (30 ml.)was purged with argon for 15 minutes, cooled in an ice-salt bath and,while stirring and continuing the argon purge, treated dropwise withconcentrated ammonium hydroxide solution (2.0 ml.). After stirring coldfor 6.5 hours, additional ammonium hydroxide solution (1.0 ml.) wasadded and the mixture was capped and left in the refrigerator for 18hours. The mixture was acidified to pH 2 with 5% potassium bisulfatesolution. The product was extracted into dichloromethane (3×50 ml.). Thecombined organic extracts were dried (magnesium sulfate), filtered andfreed of solvent in vacuo leaving a white foam. Ether and hexane wereadded and the suspension was stirred under an argon atmosphere for 1hour. A white solid was harvested by filtration, washed with more etherand hexane, and dried in vacuo to give 1.531 g. of product as a whitefoam; m.p. 71°-90° C.; R_(f) =0.41 (10 % methanol in methylenechloride+2 drops acetic acid/5 ml.); α!_(D) =+3.5° (c=0.75, methanol).

Anal. calc'd. for C₁₈ H₂₄ N₂ O₄ S: C,59.32; H,6.64; N,7.69; S,8.80;Found: C,59.02; H,6.77; N,7.67; S,8.70. HPLC: R_(T) =6.1 min., 62%aqueous methanol containing 0.2% phosphoric acid, 1.5 ml. min., detectedat 220 mm, YMC S-3 (ODS), 6.0×150 mm, 3 micron spherical end cappedcolumn. H.I.>>95%.

EXAMPLE 26 (3S)-2,3,4,5-Tetrahydro-3-(2-mercapto-3-(1-naphthalenyl)-1-oxopropyl!amino!-2-oxo-1H-benzazepine-1-aceticacid

a) (Acetylamino)(1-naphthalenylmethyl)propanedioic, diethyl ester

To a solution of sodium ethoxide (21% in ethanol, 4.613 gm, 67.8 mmol)in ethanol (100 ml) was added diethyl acetamidomalonate (14.74 gm, 67.8mmol), then 1-(bromomethyl)napthalene (10.0 gm, 45.2 mmol). The solutionwas stirred at room temperature for one hour. The reaction mixture wasthen concentrated to an orange oil. The oil was dissolved in ethylacetate and washed with 50% saturated ammonium chloride water and brine,then dried over sodium sulfate, filtered and concentrated to afford anorange solid. The solid was recrystallized from ethyl acetate and hexaneto afford beige crystals contaminated with malonate. The solid wasdissolved in 50% ethyl acetate in hexane and purified by flashchromatography on Merck silica gel in 50% ethyl acetate in hexane. Thosefractions containing pure product were combined and concentrated toafford 10.225 g. of product as a white solid; m.p. 105°-108° C.; R_(f)=0.57 (50% ethyl acetate in hexane).

b) α-Amino-1-naphthaleneoropanoic acid

A solution of the product from part (a) (16.182 gm., 47.5 mmol) wassuspended in 48% hydrogen bromide (100 ml) and refluxed under argon for14 hours. The hydrogen bromide salt of the product was filtered out ofsolution as a white solid, then taken up in hot (50° C.) water (500 ml)and the solution neutralized with concentrated ammonium hydroxide. Theproduct precipitated out of solution as a fine white solid. Uponfiltration and drying under high vacuum overnight (18 hours), 8.335 g.of product was obtained as a fluffy white solid; m.p. 264° C.

c) α-Bromo-1-naphthalenepropanoic acid

To a solution of the product from part (b) (4.000 g., 18.6 mmol) andpotassium bromide (7.63 g., 63.2 mmol) in 2.5N sulfuric acid (35 ml)kept at 0° C. was added sodium nitrite (1.92 g., 27.8 mmol) over onehour. The mixture was stirred for an additional hour at 0° C., then waswarmed to room temperature and stirred for 2.5 hours. The reactionmixture was then extracted with ether (3×). The ether layers werecombined and washed with water and brine, then dried over sodiumsulfate, filtered and concentrated to give an orange oil. The oil waspurified by flash chromatography on Merck silica gel in 70% ethylacetate in hexane with 1% acetic acid added to reduce tailing. Thosefractions containing the bromide were combined and concentrated toafford slightly contaminated product as an orange oil which solidifiedupon sitting overnight. R_(f) =0.40 (40% ethyl acetate in hexane with 1%acetic acid).

d) α-(Acetylthio)-1-naphthaleneiropanoic acid

To a slurry of potassium thioacetate (0.912 g., 8.00 mmol) inacetonitrile (300 ml) at 0° C. was added the product from part (c)(2.030 g., 7.27 mmol) as a solution in acetonitrile (3 ml). The solutionwas stirred for one hour at 0° C., then was warmed to room temperatureand stirred for 15 hours. Potassium bromide was then filtered out of thereaction mixture and the filtrate concentrated to afford an orange oil.The oil was dissolved in ethyl acetate and washed with 10% potassiumbisulfate and brine, then dried over sodium sulfate, filtered andconcentrated to afford an orange oil. The oil was purified by flashchromatography on Merck silica gel in 50% ethyl acetate in hexane with1% acetic acid added to reduce tailing. Those fractions containingproduct were all contaminated with a compound with an R_(f) =0.43. Thosefractions were pooled and concentrated to give an orange oil. The crudeproduct was purified via the dicyclohexylamine salt by dissolving theorange oil in ether and adding an equivalent of dicyclohexylamine (18.13g., 100 mmol) to the solution. The dicyclohexylamine salt was obtainedin 2 crops of brown crystals (1.450 gm) still slightly contaminated withimpurity. The crystals were suspended in ethyl acetate and shaken with10% potassium bisulfate (3×). The organic layer was then washed withwater and brine, then dried over sodium sulfate filtered andconcentrated to afford 875 mg. of product as a yellow oil; R_(f) =0.40(40% ethyl acetate in hexane with 1% acetic acid).

e) (3S)-2,3,4,5-Tetrahydro-3-2-(acetylthio)-3-(1-naphthalenyl)-1-oxoiropyl!amino!-2-oxo-1H-1-benzazepine-1-aceticacid

The racemic acid product from part (d) (338 mg., 1.23 mmol) and(S)-2,3,4,5-tetrahydro-3-amino-2-oxo-1H-1-benzazepine-1-acetic acid,ethyl ester prepared as described by watthey et al., J. Med. Chem., 28,p 1511-1516 (1985)! (321 mg., 1.23 mmol) were dissolved in methylenechloride (11 ml) at room temperature under argon. The mixture was cooledto 0° C. and treated with hydroxybenzotriazole hydrate (166 mg, 1.23mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (259 mg, 1.35mmol). After stirring for 1 hour, the mixture was warmed to roomtemperature and stirred an additional 4 hours. The volatiles wereevaporated and the residue was dissolved in ethyl acetate and washedsuccessively with 1N hydrochloric acid, water, saturated sodiumbicarbonate, and brine. The organic layer was dried (sodium sulfate),filtered, and concentrated and the residue was flash chromatographed(Merck silica gel) eluting with 50% ethyl acetate in hexanes to give 510mg. of product as an oil (1:1 mixture of diastereomers). R_(f) =0.40 (5%acetic acid in ethyl acetate).

f) (3S)-2,3,4,5-Tetrahydro-3-2-mercapto-3-(1-naphthalenyl)-1-oxopropyl!amino!-2-oxo-1H-1-benzazepine-1-aceticacid

A solution of the product form part (e) (508 mg., 0.98 mmol) in methanol(6 ml., deoxygenated via argon bubbling) was cooled to 0° C. and treatedwith 1N sodium hydroxide (6 ml., deoxygenated via argon bubbling). Theresulting mixture was stirred under argon for 1 hour. The solution wasacidified with 10% potassium bisulfate and extracted with ethyl acetate.The organic layer was washed with brine, dried (sodium sulfate),filtered and concentrated to give a clear oil. This residue was flashchromatographed (Merck silica gel) eluting with 1% acetic acid in 1:1hexanes/ethyl acetate. The fractions containing pure product werecombined, concentrated, azeotroped with ethyl acetate, and washed withwater to remove the acetic acid. The organic layer was dried (sodiumsulfate), filtered and concentrated. The residue was taken up in ethylacetate and triturated with ethyl ether and hexane. The solvent wasremoved and the residue was slurried in hexane, stripped, and dried invacuo to give 327 mg of product as a white powdery foam; R_(f) =0.64 (5%acetic acid in ethyl acetate); α!_(D) =-187.3° (c=0.43, chloroform).

Anal. calc'd for C₂₅ H₂₃ N₂ O₄ S.0.42 H₂ O: C,65.98; H,5.28; N,6.16;S,7.05; Found: C,66.29; H,5.29; N,5.85; S,6.65.

HPLC: t_(R) =12.3 min (48.1%) and 14.4 min (51.8 %) (λ=220 nm), YMC S-3ODS (C-18) 6.0×150 mm; 68% (10% water-90% methanol-0.2 % phosphoricacid)/32% (90% water-10% methanol.2% phosphoric acid), flow rate=1.5ml/min, isocratic.

EXAMPLE 27 S-(R*,R*)!-3-2-(Acetylthio)-1-oxo-3-phenylpropyl!amino!-2,3,4,5-tetrahydro-1-oxo-1H-benzazapine-1-aceticacid

The product from Example 6 (799 mg., 2.0 mmol.) was added to ade-oxygenated (argon bubbling) solution of potassium bicarbonate (378mg., 3.8 mmol.) in water (25 ml.). Upon dissolution of the startingmaterial, acetic anhydride (1.5 ml., 1.62 g., 15.9 mmol.) was added. Amilky white solution was obtained which eventually produced a gum. Afterstirring at room temperature for minutes, the mixture was acidified with10% hydrochloric acid and extracted with ethyl acetate. The ethylacetate extract was washed with water (3 times) and brine, then dried(sodium sulfate), filtered, and stripped. The residue was flashchromatographed (Merck silica gel, 1% acetic acid in ethyl acetate) andthe desired fractions were stripped, azeotroped with ethyl acetate (3times), taken up in a small volume of ethyl acetate and triturated withhexane. The solvent was stripped and the residue was slurried andstripped twice from hexane to give the title compound as a hard whitefoam. TLC (1% acetic acid in ethyl acetate) R_(f) =0.41; α!_(D) =-190.8°(c=0.68, chloroform).

Anal. calc'd. for C₂₃ H₂₄ N₂ O₅ S.0.13 C₄ H₈ O₂.0.5 H₂ O: C, 61.28; H,5.69; N, 6.08; S, 6.96; Found: C, 61.18; H, 5.64; N, 5.90; S, 6.70.

EXAMPLES 28-30

Following the procedure of Example 27 but employing benzoyl chloride asthe acylating agent, S-(R*,R*)!- 3-2-(benzoylthio)-1-oxo-3-phenylpropyl!amino!-2,3,4,5-tetrahydro-2-oxo-1H-benzazepine-1-aceticacid was obtained; m.p. 170°-171° C.; α!_(D) =-244° (c=0.30,chloroform). TLC (hexane:ethyl acetate:acetic acid, 40:60:1) R_(f)=0.31.

Anal. calc'd. for C₂₈ H₂₆ N₂ O₅ S.0.1 C₄ H₈ O₂ 0.2H₂ O: C, 66.24; H,5.32; N, 5.44; S, 6.23; Found: C, 66.28; H, 5.23; N, 5.40; S, 6.18.

Following the procedure of Example 27 but employing propionic anhydrideas the acylating agent, S-(R*,R*)!-2,3,4,5-tetrahydro-3- 1-oxo-2-(1-oxpropyl)thio!-3-phenylpropyl!amino!-2-oxo-1H-benzazepine-1-aceticacid was obtained; m.p. 156-20 -157° C.; α!_(D) =-210° (c=0.31,chloroform). TLC (hexane:ethyl acetate:acetic acid, 40:60:1) R_(f)=0.34.

Anal. calc'd. for C₂₄ H₂₆ N₂ O₅ S.0.07 C₄ H₈ O₂ : C, 63.30; H, 5.81; N,6.08; S, 9.96; Found: C, 63.32; H, 5.77; N, 5.90; S, 6.96.

Following the procedure of Example 27 but employing trimethylaceticanhydride as the acylating agent, S-(R*,R*)!-3- 2-(2,2-dimethyl-1-oxopropyl)thio!-1-oxo-3-phenylpropyl!amino!-2,3,4,5-tetrahydro-2-oxo-1H-benzazepine-1-aceticacid was obtained; m.p. 86°-90° C.; α!_(D) ==31 190° (c=3.06,chloroform). TLC (hexane:ethyl acetate:acetic acid, 30:70:1) R_(f)=0.42.

Anal. calc'd. for C₂₆ H₃₀ N₂ O₅ S.0.2 C₆ H₁₄.0.25 H₂ O: C, 64.78; H,6.65; N. 5.50; S, 6.36; Found: C, 64.79; H, 6.56; N, 5.53; S, 6.30.

EXAMPLE 31 S-(R*,R*)!-3,4-Dihydro-3-(2-mercapto-1-oxo-3-phenylpropyl)amino!-4-oxo-1,5-benzoxazepine-5(2H)-propanoicacid

a) (S)-3-(Dimethylethoxy)carbonyl!amino!-3,4-dihydro-4-oxo-1,5-benzoxazepine-5(2H)-propanoicacid, ethyl ester

A solution of (S)-3-(dimethylethoxy)carbonyl!amino!-2,3-dihydro-1,5-benzoxazepin-4(5H)-oneprepared as described in Example 13(c), 1.49 g., 5.35 mmol.) intetrahydrofuran:t-butanol (2:1, 21 ml.) was cooled to 0° C. and treatedwith ethyl acrylate (0.81 ml. 7.50 mmol., 1.4 eq.) and then 1.0Nt-butanol, potassium salt (535 μl., 0.1 eq.). The reaction mixture wasstirred at 0° C. for 15 minutes then at room temperature for 2.5 hoursunder argon. An additional amount of 1.0N t-butanol, potassiumsalt/tetrahydrofuran (270 μl., 0.05 eq.) was added to the reaction. Thereaction was stirred at room temperature for 45 minutes and then heatedto 60° C. for 2 hours. The reaction was quenched with 25% ammoniumchloride (50 ml.) and extracted with ethyl acetate (2×100 ml.). Thecombined organics were washed with 25% ammonium chloride (50 ml.), water(50 ml.), and brine (50 ml.), dried over magnesium sulfate, filtered andconcentrated to yield a clear syrup. The residue showed two spots byTLC.

The reaction was restarted by treating a solution of the mixture (1.42g., 5.10 mmol.) in tetrahydrofuran:t-butanol (2:1, 15 ml.) cooled to 0°C., with ethyl acrylate (0.77 ml., 7.14 mmol., 1.4 eq.) and then 1.0Nt-butanol, potassium salt/tetrahydrofuran (510 μl., 0.1 eq.). Thereaction mixture was stirred at 0° C. for 15 minutes then at roomtemperature for 3 hours. The reaction was quenched with 25% ammoniumchloride (50 ml.) and extracted with ethyl acetate (2×100 ml.). Thecombined organics was washed with 25% ammonium chloride (50 ml.), water(50 ml.), and brine (50 ml.), dried over magnesium sulfate, filtered andconcentrated to yield a yellow syrup. The residue was purified bychromatography on a 5×15 cm. silica gel column eluting with 30% ethylacetate/hexane mixture (2l.). The desired fractions were combined andconcentrated to afford 1.40 g. of the title compound as a clear syrup.TLC (5% methanol/chloroform) R_(f) =0.63.

b) (S)-3-Amino-3,4-dihydro-4-oxo-1,5-benzoxazerine-5(2H)-oropanoic acid,ethyl ester, hydrochloride salt

The product from part (a) (1.4 g., 3.7 mmol.) was treated with 4.0Mhydrochloric acid/dioxane (20 ml., 80 mmol.) and cooled to 0° C. Theresultant solution was stirred at 0° C. for 30 minutes, then at roomtemperature for 2 hours. The reaction mixture was concentrated, strippedwith ethyl ether (twice), azeotroped with toluene (three times) anddried in vacuo for 4 hours affording 1.05 g. of title compound.

c) (S-(R*,R*)!-3-2-(Acetylthio)-1-oxo-3-phenylprolyl!amino!-3,4-dihydro-4-oxo-1,5-benzoxazepine-5(2H)-propanoicacid, ethyl ester

(S)-2-(Acetylthio)benzenepropanoic acid, dicyclohexylamine salt (1.8 g.,4.40 mmol.) was suspended in ethyl acetate (100 ml.) and washed with 5%potassium bisulfate (5×25 ml.) and brine (30 ml.), dried (anhydrousmagnesium sulfate), filtered, evaporated to dryness and dried in vacuoto give the free acid.

This free acid was dissolved in dry methylene chloride (10 ml.), cooledto 0° C. (ice-salt bath) and treated with a solution of the product frompart (b) (1.05 g., 3.33 mmol.) in dry methylene chloride (25 ml.),followed by triethylamine (0.62 ml., 4.44 mmol., 1.3 eq.) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(1.96 g., 4.44 mmol., 1.3 eq.). The reaction mixture was stirred at 0°C. for 1 hour then at room temperature overnight. The reaction mixturewas concentrated to dryness, diluted with ethyl acetate (150 ml.) andwashed with 5% potassium bisulfate (2×50 ml.), water (2×50 ml.), andbrine (50 ml.), dried (anhydrous magnesium sulfate), filtered, andevaporated to dryness. The crude product was chromatographed on a silicagel column (5×15 cm), eluting with 30% ethyl acetate/hexane. The desiredfractions were combined and concentrated, affording 740 mg. pureproduct. TLC (10% methanol in chloroformm) R_(f) =0.74.

d) S-(R*,R*)!-3,4-Dihydro-3-(2-mercapto-1-oxo-3-phenylpropyl)amino!-4-oxo-1,5-benzoxazpeine-5(2H)-prolanoicacid

A solution of the product from part (c) (740 mg., 1.53 mmol.) inmethanol (15 ml.) was cooled to 0° C. (ice-salt bath), purged with argonfor 30 minutes and then treated dropwise with a previously purged(argon, 30 minutes) solution of 1.0N sodium hydroxide (6.1 ml., 4 eq.)maintaining the bubbling of argon throughout the addition and length ofthe reaction. The reaction mixture was stirred at 0° C. for 1 hour,acidified at 0° C. with 5% potassium bisulfate (150 ml.) to pH 1.5 andthen extracted with ethyl acetate (3×100 ml.). The combined organicextracts were washed with brine (100 ml.), dried (anhydrous sodiumsulfate), filtered, evaporated to dryness and dried in vacuo to a whitefoam (612 mg.). The residue was purified by column chromatography on a5×15 cm. silica gel column eluting with 0.5% acetic acid in ethylacetate. The residue was dissolved in methylene chloride (5 ml.) andstripped with hexane (5 times) on the rotovap, scratching the mixture toform a white foam/solid. The solid was dried in vacuo overnight to give590 mg. of product. TLC (1% acetic acid in ethyl acetate) R_(f) =0.42.α!_(D) =-127.6° (c=1.12, methanol).

Anal. calc'd. for C₂₁ H₂₂ N₂ O₅ S.0.03 H₂ O: C, 60.86; H, 5.36; N, 6.75;S, 7.73; Found: C, 61.08; H, 5.68; N, 6.45; S, 7.51.

EXAMPLE 32 2R- 2α,3α(S*)!!-3,4-Dihydro-3-(2-mercapto-1-oxo-3-phenylpropyl)amino!-2-methyl-4-oxo-1,5-benzoxazepine-5(2H)-aceticacid

a) N- (1,1-Dimethylethoxy)carbonyl!-O-(2-nitrophenyl)-L-threonine

A solution of N- (1,1-dimethylethoxy)carbonyl!-L-threonine (5.02 g.,22.9 mmol.) in dry dimethylformamide (10 ml.) was added dropwise over aperiod of 30 minutes to a cooled (0° C.) suspension of 60% sodiumhydride (1.93 g., 48.25 mmol., 2.11 eq.) in dry dimethylformamide (40ml.). The reaction was stirred at 0° C. until the frothing subsided(about 3.5 hours). The reaction mixture was treated dropwise with1-fluoro-2-nitrobenzene (2.67 ml., 25.2 mmol., 1.1 eq.) over a period of20 minutes and stirred at 0° C. under argon for 2 hours. The reactionmixture was then placed in the cold room (5° C.) and stirred overnight.The reaction mixture was poured into ice-water (500 ml.) and extractedwith ethyl ether (2×200 ml.). The aqueous phase was brought to pH 1.0with 6N hydrochloric acid (200 ml.) and extracted with ethyl acetate(3×300 ml.). The combined ethyl acetate extracts were washed with water(2×300 ml.), and brine (300 ml.), dried (anhydrous sodium sulfate),filtered, evaporated to dryness and dried in vacuo. The crude residuewas loaded onto celite and purified by chromatography on a 10×20 cm.silica gel column. Elution with methylene chloride (3 l.), 99:1methylene chloride:methanol (2 l.), 95:5 methylene chloride:methanol,and 100:5:0.5 methylene chloride:methanol:acetic acid (5 l.) gave 6.07g. of title compound. TLC (methylene chloride:methanol:acetic acid,100:5;0.5) R_(f) =0.16.

b) N- (1,1-Dimethylethoxy)carbonyl!-O-(2-aminophenyl)-L-threonine

A solution of the product from part (a) (1.0 g., 2.94 mmole) in drymethanol (20 ml.) was treated with 10% palladium on carbon catalyst (35mg.) and hydrogenated at 40 psi for 5.5 hours. The reaction was notcomplete so an additional 50 mg. of 10% palladium on carbon catalyst wasadded and the reaction mixture was hydrogenated for an additional 1.5hours. The reaction mixture was filtered through a celite pad in amillipore unit, washing the pad with methanol. The dark filtrate wasevaporated to dryness and dried in vacuo to give 0.856 g. of titleproduct as a dark solid. TLC (methylene chloride:methanol:acetic acid,20:1:1) R_(f) =0.16.

c) (2R-cis)-3-(Dimethylethoxy)carbonyl!amino!-2,3-dihydro-2-methyl-1,5-benzoxazepin-4(5H)-one

A solution of the product from part (b) (0.8 g., 2.58 mmol.) in drydimethylformamide (6 ml.) was treated with1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (495 mg., 2.58 mmol.) andstirred at room temperature for 3 hours. The reaction mixture waspartitioned between ethyl acetate (50 ml.) and 50% sodium bicarbonatesolution (50 ml.). The aqueous layer was separated and extracted withethyl acetate (2×50 ml.). The combined organic extracts were washed withwater (3×50 ml.) and brine (50 ml.), dried (anhydrous magnesiumsulfate), filtered, evaporated and dried in vacuo to yield a crudeyellow solid. The crude product was chromatographed on a silica gelcolumn(5×15 cm.), eluting with 25% ethyl acetate/hexane to give 568 mg.of title compound as an off white solid. TLC (ethyl acetate:hexane, 1:1)R_(f) =0.47.

d) (2R-cis)-3-(Dimethylethoxy)carbonyl!amino!-3,4-dihydro-2-methyl-4-oxo-1,5-benzoxazepine-5(2H)-aceticacid, ethyl ester

A solution of the product from part (c) (319 mg., 1.09 mmol.) and ethylbromoacetate (151.3 μl. 1.36 mmol., 1.25 eq.) in dry tetrahydrofuran (3ml.) was added to a cooled 0° C. suspension of 60% sodium hydride (53mg., 1.32 mmol., 1.21 eq., washed with hexane, 3 times) in drytetrahydrofuran (2 ml.) over a period of 5 minutes. The reaction mixturewas stirred at 0° C. for 1 hour and then at room temperature for 30minutes. The reaction mixture was quenched with 25% ammonium chloridesolution (5 ml.) and extracted with methylene chloride (2×20 ml.). Thecombined organics were washed with 25% ammonium chloride solution (10ml.) and brine (10 ml.), dried (anhydrous magnesium sulfate), filtered.concentrated and dried in vacuo to yield 400 mg. of title product. TLC(ethyl acetate:hexane, 1:1) R_(f) =0.55.

e) (S)-3-Amino-3,4-dihydro-2-methyl-4-oxo-1,5-benzoxazepine-5(2H)-aceticacid, ethyl ester, hydrochloride salt

4.0M Hydrochloric acid in dioxane (5.5 ml., 22 mmole, 20.8 eq.) wasadded to the product from part (d) (400 mg., 1.06 mmol.) cooled to 0° C.The resultant solution was stirred at 0° C. for thirty minutes, then atroom temperature for 3 hours. The reaction mixture was removed byrotovap, concentrated with ethyl ether (3×10 ml.) and dried in vacuoover sodium hydroxide pellets overnight to yield 350 mg. of titleproduct. TLC (methylene chloride:methanol, 9:1) R_(f) =0.49.

f) 2R- 2α,3α(S*)!!-3-2-(Acetylthio)-1-oxo-3-phenylpropyl!amino!-2-methyl-4-oxo-1,5-benzoxazepine-5(2H)-aceticacid

A suspension of (S)-2-(acetylthio)benzenepropanoic acid,dicyclohexylamine salt (495 mg., 1.22 mmol., 1.1 eq.) in ethyl acetate(30 ml.) was washed with 5% potassium bisulfate (5×5 ml.) and brine (10ml.), dried (anhydrous magnesium sulfate), filtered, evaporated todryness and dried in vacuo to give the free acid as a clear syrup (278mg.) in quantitative yield.

This free acid was dissolved in dry methylene chloride (10 ml.), cooledto 0° C. (ice-salt bath) and treated with a solution of the product frompart (e) (350 mg., 1.11 mmol.) in dry methylene chloride (2 ml.),followed by triethylamine (163 μl., 1.17 mmol., 1.05 eq.) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(515.5 mg., 1.17 mmol., 1.05 eq.). The reaction mixture was stirred at0° C. for 1 hour then at room temperature for 3.5 hours. The reactionwas not complete by TLC so an additional amount of triethylamine (54μl., 0.389 mmol.) and benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (172 mg., 0.389 mmol.) was added and the reactionwas stirred for 1 hour. The reaction mixture was concentrated todryness, dissolved in ethyl acetate, washed with 0.5N hydrochloric acid(2×10 ml.), water (10 ml.), and brine (10 ml.), dried (anhydrousmagnesium sulfate), filtered, and evaporated to dryness. The crudeproduct was chromatographed on a silica gel column (3×16 cm.), elutingwith 20% ethyl acetate/hexane. The desired fractions were combined andconcentrated, affording 378 mg. of pure title product. TLC (ethylacetate:hexane, 1:1) R_(f) =0.48.

a) 2R- 2α,3α(S*)!!-3,4-Dihydro-3-(2-mercapto-1-oxo-3-phenylpropyl)amino!-2-methyl-4-oxo-1,5-benzoxazepine-5(2H)-aceticacid

A solution of the product from part (f) (297 mg., 0.61 mmol.) inmethanol (4 ml.) was purged with argon for 30 minutes, cooled to 0° C.(ice-salt bath) then treated dropwise with a previously purged (argon,30 minutes) solution of 1.0N sodium hydroxide (2.45 ml., 4 eq.)maintaining the bubbling of argon throughout the addition and length ofthe reaction. The reaction mixture was stirred at 0° C. for 1 hour,acidified at 0° C. with 5% potassium bisulfate (20 ml.) to pH 1.5 andthen extracted with ethyl acetate (2×50 ml.). The combined organicextracts were washed with brine (25 ml.), dried (anhydrous sodiumsulfate), filtered, evaporated to dryness and dried in vacuo to yield aglassy oil (351 mg.). The crude residue was dissolved in methylenechloride (5 ml.) and treated portionwise with hexane (50 ml.),scratching the mixture to form a solid. The supernatant was decanted andthe solids triturated with more hexane (50 ml.) and pentane (2×100 ml.),stirring with the first 100 ml. of pentane for 4 hours and the next 100ml. overnight under argon. The pentane was decanted and the whiteamorphous solid was dried in vacuo overnight to give 240 mg., of titleproduct. TLC (2% acetic acid in ethyl acetate) R_(f) =0.48; α!_(D)=-101.1 (c=1, methanol).

Anal. calc'd. for C₂₁ H₂₂ N₂ O₅ S.0.40 C₄ H₈ O₂.0.08 H₂ O: C, 60.36; H,5.65; N, 6.23; S, 7.13; Found: C, 60.17; H, 5.57; N, 6.16; S, 7.45.

EXAMPLE 33

Following the procedure of Example 32 but starting withallo-L-threonine, 2S- 2α,3β(R*)!!-3,4-dihydro-3-(2-mercapto-1-oxo-3-phenylpropyl)amino!-2-methyl-4-oxo-1,5-benzoxazepine-5(2H)-aceticacid was obtained; α!_(D) =-174.3° (c=0.89, methanol) TLC (1% aceticacid in ethyl acetate) R_(f) =0.43.

EXAMPLE 34 (2S)-3-(2-Mercapto-1-oxo-3-phenylpropyl)amino!-3,4,5,6-tetrahydro-2-oxo-1-benzazocine-1(2H)-aceticacid

a) 1-Benzosuberone, oxime

A solution of hydroxylamine hydrochloride (2.39 g., 34.33 mmole, 1.1eq.) in water (16 ml.) was added to a solution of 1-benzosuberone (4.67ml., 31.21 mmole) in pyridine (9.0 ml.) and ethanol (16 ml.). Thereaction mixture was refluxed (bath temperature 105° C.) for 35 minutes.The reaction mixture was cooled, diluted with ethyl acetate (100 ml.)and water (40 ml.) and the layers were separated. The aqueous layer wasextracted with ethyl acetate (2×50 ml.). The combined organic extractswere washed with 1N hydrochloric acid (3×100 ml.), dried (anhydrousmagnesium sulfate), filtered, and concentrated to obtain a crude offwhite solid (5.60 g.). The residue was purified by chromatography on10×20 cm. silica gel column. Elution with hexane (2 l), followed by 10%ethyl acetate/hexane (5 l.) afforded 4.40 g. of title compound as anoff-white solid. TLC (10% ethyl acetate/hexane) R_(f) =0.35.

b) 3,4,5,6-Tetrahydro-1-benzazocin-2(1H)-one

Concentrated sulphuric acid (8.8 ml.) was added in one portion to asuspension of the product from part (a) (4.33 g., 24.71 mmol.) inglacial acetic acid (4.4 ml.). The temperature rose to 83° C. and thereaction mixture was heated to 160° C. (oil bath) for 10 minutes. Thereaction mixture was allowed to cool to room temperature and was thenpoured into ice-water (100 ml.). The reaction mixture was adjusted to pH11 with 10N sodium hydroxide solution. The mixture was diluted withethyl acetate (250 ml.) and water (100 ml.) and the layers wereseparated. The aqueous layer was extracted with ethyl acetate (3×100ml.). The combined ethyl acetate extracts were washed with water (150ml.) and brine (150 ml.), dried (anhydrous sodium sulfate), filtered andconcentrated to yield 2.8 g. of title product. TLC (ethyl acetate) R_(f)=0.33.

c) 3,4,5,6-Tetrahydro-3-bromo-1-benzazocin-2(1H)-one

A solution of the product from part (b) (8.31 g., 47.42 mmole) inchloroform (115 ml.) was cooled to 0° C., treated with phosphoruspentachloride (11.36 g., 54.53 mmole, 1.15 eq.) and iodine (114 mg.) andstirred for 30 minutes at 0° C. under argon. The yellow reaction mixturewas treated with bromine (2.92 ml., 56.90 mmole, 1.2 eq.), warmed toroom temperature and refluxed under argon for 3.5 hours. The reactionmixture was allowed to cool to room temperature and added to ice-water(100 ml.). The layers were separated and the chloroform layer was washedwith water (100 ml.), dried over magnesium sulfate, filtered andconcentrated. The crude residue was recrystallized from hot ethylacetate affording 8.69 g. of title product. TLC (ethyl acetate:hexane,1:1) R_(f) =0.36.

d) 3,4,5,6-Tetrahydro-3-azido-1-benzazocin-2(1H)-one

A solution of the product from part (c) (6.87 g., 27.03 mmole) andsodium azide (2.28 g., 35.14 mmole, 1.3 eq.) in dimethylsulfoxide (130ml.) was stirred at 60° C. (oil bath) under argon for 5 hours. Thereaction mixture was cooled to room temperature and poured into coldwater (400 ml.) and stirred for 15 minutes. The precipitate wasfiltered, washing the solids with water (1 l.) and dried overnight invacuo over drierite to give the title product. TLC (ethylacetate:hexane, 1:1) R_(f) =0.63.

e) 3-Azido-3,4,5,6-tetrahydro-2-oxo-1-benzazocine-1(2H)-acetic acid,ethyl ester

A solution of the product from part (d) (5.454 g., 25.22 mmole) andethyl bromoacetate (3.5 ml., 31.53 mmole, 1.25 eq.) in drytetrahydrofuran (50 ml.) was added to a cooled (0° C.) suspension of 60%sodium hydride 1.23 g., 30.77 mmole, 1.22 eq.; washed with hexane (3×10ml.)! in dry tetrahydrofuran (15 ml.) over a period of 15 minutes. Themixture was stirred at 0° C. for 1 hour and then at room temperature for30 minutes. The reaction mixture was quenched with 25% ammonium chloridesolution (100 ml.) and extracted with ethyl acetate (2×250 ml.). Thecombined ethyl acetate extracts were washed with 25% ammonium chloridesolution (100 ml.) and brine (100 ml.), dried (anhydrous magnesiumsulfate), filtered, and concentrated to yield the title compound as ayellow oil. TLC (35% ethyl acetate/hexane) R_(f) =0.35.

f) 3-Amino-3,4,5,6-tetrahydro-2-oxo-1-benzazocine-1(2H)-acetic acid,ethyl ester

A solution of the product from part (e) (9.0 g., 29.83 mmole) inabsolute ethanol (50 ml.) was treated with 10% palladium on carboncatalyst (900 mg.) and hydrogenated at 45 psi for 5 hours, venting theParr bottle twice in the first 1.5 hours. The mixture was filteredthrough a millipore unit, washing thoroughly with ethanol. The clearfiltrate was evaporated to dryness and dried in vacuo to afford 7.59 g.of the title product as a thick yellow syrup. TLC (10%methanol/methylene chloride) R_(f) =0.29.

a) (2S)-3-2-(Acetylthio)-1-oxo-3-phenylpropyl!-amino!-3,4,5,6-tetrahydro-2-oxo-1-benzazocine-1(2H)-aceticacid, ethyl ester

A suspension of (S)-2-(acetylthio)benzenepropanoic aciddicyclohexylamine salt (2.1 g., 5.18 mmole. 1.1 eq.) in ethyl acetate(100 ml.) was washed with 5% potassium bisulfate (5×25 ml.) and brine(30 ml.), dried (anhydrous magnesium sulfate), filtered, evaporated todryness and dried in vacuo to give the free acid as a clear syrup (1.24g.) in quantitative yield.

This free acid was dissolved in dry methylene chloride (45 ml.), cooledto 0° C. (ice-salt bath) and treated with a solution of the product frompart (f) (1.3 g., 4.71 mmole) in dry methylene chloride (10 ml.),followed by triethylamine (723 μl., 5.18 mmol., 1.1 eq.) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(2.29 g., 5.18 mmol., 1.1 eq.). The reaction mixture was stirred at 0°C. for 1 hour then at room temperature overnight. The reaction mixturewas concentrated to dryness, diluted with ethyl acetate (125 ml.),washed with 0.5N hydrochloric acid (2×25 ml.), water (25 ml.), and brine(25 ml.), dried (anhydrous magnesium sulfate), filtered, and evaporatedto dryness. The crude product was chromatographed on a silica gel column(3×16 cm.), eluting with 30% ethyl acetate/hexane. The desired fractionswere combined and concentrated, affording 1.77 g. of pure titlecompound. (1:1 mixture of diastereoisomers). TLC (ethyl acetate:hexane,1:1) R_(f) =0.39.

h) (2S)-3-(2-Mercapto-1-oxo-3-phenylpropyl)amino!-3,4,5,6-tetrahydro-2-oxo-1-benzazocine-1(2H)-aceticacid

A solution of the product from part (g) (1.75 g., 3.62 mmole) inmethanol (25 ml.) was purged with argon for 30 minutes, cooled to 0° C.(ice-salt bath) then treated dropwise with a previously purged (argon,30 minutes) solution of 1.0N sodium hydroxide (14.5 ml., 4 eq.)maintaining the bubbling of argon throughout the addition and length ofthe reaction. The reaction mixture was stirred at 0° C. for 1 hour,acidified at 0° C. with 5% potassium bisulfate (200 ml.) to pH 1.5 andthen extracted with ethyl acetate (2×200 ml.). The combined organicextracts were washed with brine (200 ml.), dried (anhydrous sodiumsulfate), filtered, evaporated to dryness and dried in vacuo to yield awhite foam (1.67 g.). The crude residue was dissolved in methylenechloride (10 ml.) and treated portionwise with hexane (50 ml.),scratching the mixture to form a solid. The supernatant was decanted andthe solids triturated with more hexane (50 ml.) and pentane (2×100 ml.),stirring with the first 100 ml. of pentane for 4 hours and the next 100ml. overnight under argon. The pentane was decanted and the whiteamorphous solid was dried in vacuo overnight to give 1.388 g. of titleproduct (1:1 mixture of diastereoisomers); m. p. 107°-111° C.; α!_(D)=+28.3° (c=1.0, methanol). TLC (methylene chloride:methanol:acetic acid,20:1:1) R_(f) =0.44.

EXAMPLE 35 4S- 4α,7α(R*),10aβ!!-Decahydro-7-(2-mercapto-1-oxo-3-phenylpropyl)amino!-6-oxopyrido1,2-alazepine-4-carboxylic acid

a) (S)-2-Phthalimido-4-pentenoic acid, dicyclohexylamine salt

A homogeneous solution of (S)-2-amino-4-pentenoic acid (2.988 g., 25.9mmol) and sodium carbonate (2.600 g., 24.5 mmol.) in water (55 ml.) wastreated with solid N-(carbethoxy)phthalamide (5.677 g., 25.9 mmol.).After stirring at room temperature for 2.5 hours, the mixture wasacidified with 10% hydrochloric acid and extracted with ethyl acetate.The ethyl acetate extract was washed with brine, dried (sodium sulfate),filtered, and stripped. The residue was flash chromatographed twice (2%acetic acid in ethyl acetate) and the desired product fractions werecombined, stripped, and azeotroped with toluene. The residue wasdissolved in ethyl ether, treated with 5.3 ml. of dicyclohexylamine andseeded. The resulting white precipitate was collected by filtration,washed with ethyl ether, and dried in vacuo to give 7.620 g. of puretitle product; m.p. 196°-197° C.; α!_(D) =-13.9° (c=0.8, methanol). TLC(5% acetic acid in ethyl acetate) R_(f) =0.57.

b) S-(R*,R*)!-2-(2-Phthalimido-1-oxo-4-pentenyl)amino!-6-hydroxyhexanoic acid, methylester

A slurry of (S)-2-amino-6-hydroxyhexanoic acid (2.42 g., 16.4 mmole) indry methanol (60 ml.) was treated with gaseous hydrogen chloride untilthe mixture began to reflux. The homogeneous solution was then stirredat room temperature for 2.5 hours. The solvent was stripped and theresidue azeotroped three times with toluene to give crude(S)-2-amino-6-hydroxyhexanoic acid, methyl ester, hydrochloride salt asan oil. This oil was dissolved in dimethylformamide (20 ml.) andmethylene chloride (50 ml.) and treated with 4-methyl morpholine (3.20ml., 2.94 g., 29.1 mmole). This mixture was cooled to 0° C. and treatedwith (S)-2-phthalimido-4-pentenoic acid obtained from 7.0 g., 16.4 mmoleof the salt product from part (a) by partitioning between 10% potassiumbisulfate and ethyl acetate! in methylene chloride (10 ml.), followed bysolid hydroxybenzotriazole (2.22 g., 16.4 mmole) andethyl-3-(3-dimethylamino)propyl carbodiimide, hydrochloride salt (3.458g., 18.0 mmole). After stirring at 0° C. for 0.5 hour and at roomtemperature for 2 hours, the reaction was partitioned between ethylacetate and 0.5N hydrochloric acid. The ethyl acetate extract was washedsuccessively with water, 50% saturated sodium bicarbonate, and brine,then dried (sodium sulfate), filtered and stripped. The residue wasflash chromatographed (Merck silica gel, ethyl acetate) to give puretitle compound as an oil which solidified upon standing. The solid wastriturated with ethyl ether and hexane and collected by filtration togive 5.149 g. of analytically pure title product; m.p. 90°-92° C.;α!_(D) =+25.6 (c=1.1, chloroform). TLC (ethyl acetate) R_(f) =0.36.

c) S-(R*,R*)!-2- (2-Phthalimido-1-oxo-4-pentenyl)amino!-6-oxohexanoicacid, methyl ester

A -78° C. solution of oxalyl chloride (1.38 ml., 0.95 g., 7.5 mmol.) inmethylene chloride (70 ml.) was treated dropwise with a solution of drydimethylsulfoxide (2.20 ml., 2.00 g., 25.6 mmol.) in methylene chloride(2 ml.). After 10 minutes, the mixture was treated with a solution ofthe product from part (b) (5.04 g., 13.0 mmol.) in methylene chloride(15 ml.). After an additional 10 minutes, triethylamine (9.0 ml.) wasadded and the mixture was stirred at -78° C. for 5 minutes, then allowedto warm gradually to 0° C. The mixture was partitioned between ethylacetate/ethyl ether and 0.5N hydrochloric acid. The organic extract waswashed with 50% saturated sodium bicarbonate and brine, then dried(sodium sulfate), filtered and stripped. The residue was crystallizedfrom ethyl acetate/ethyl ether to afford compound 4.567 g. of titleproduct as a white solid. The mother liquor was flash chromatographed(Merck silica gel, 6/4-ethyl acetate/hexanes) and crystallized to givean additional 184 mg. of product for a total of 4.751 g.; m.p. 74°-76°C.; α!_(D) =+25.20 (c=1.3, chloroform). TLC (ethyl acetate:hexanes, 6:4)R_(f) =0.22.

d)S-(R*,R*)-1,2,3,4-Tetrahydro-(1-oxo-2-phthalimido-4-pentenyl)-2-pyridinecarboxylicacid, methyl ester

A solution of the product from part (c) (3.657 g., 9.46 mmole) andtrifluoroacetic acid (190 μl.) in methylene chloride (70 ml.) wasrefluxed under argon for 1.5 hours. The cooled mixture was washed withdilute aqueous sodium bicarbonate, dried (sodium sulfate), filtered andstripped. The residue was flash chromatographed (Merck silica gel), 1:1ethyl acetate:hexanes) to afford 3.417 g. of the title product as anoil/foam. TLC (ethyl acetate:hexanes) R_(f) =0.50.

e) 4S-(4α,7α,10aβ)!-Decahydro-9-iodo-6-oxo-7-phthalimidopyrido1,2-a!a!azepine,4-carboxylic acid, methyl ester

A solution of the product from part (d) (1.427 g., 3.87 mmole) inmethylene chloride (8.8 ml.) was added dropwise to a mixture oftrifluoromethanesulfonic acid (2.2 ml.) and trifluoromethanesulfonicanhydride (210 gl.) at room temperature. The bright yellow solution wasstirred for 5.5 hours, then poured into ice water and extracted withethyl acetate. The ethyl acetate extract was washed with brine, dried(sodium sulfate), filtered and stripped. The crude residue(predominantly a mixture of carboxylic acids) was dissolved in methanol(3 ml.) and methylene chloride (20 ml.) and treated with excess etherealdiazomethane for 25 minutes. The excess diazomethane was removed viaargon bubbling and the solvent was stripped. The residue was dissolvedin methyl ethyl ketone (40 ml.) and treated with sodium iodide (2.48g.). After stirring at room temperature for 1 hour, the mixture waspartitioned between ethyl acetate and water which contained a smallamount of sodium bisulfite. The organic layer was washed with brine,dried (sodium sulfate), filtered and stripped. The residue was flashchromatographed (Merck silica gel, 1:1 ethyl acetate:hexanes followed by6:4 ethyl acetate: hexanes) to give 1.125 g. of title product as a whitefoam; α!_(D) =-17.1° (c=0.7, chloroform). TLC (ethyl acetate:hexanes,6:4) R_(f) =0.43.

In addition 206 mg. of4S-(4α,7α,10aβ)!-1,2,3,4,6,7,8,10a-octahydro-6-oxo-7-phthalimidopyrido1,2-a!azepine, 4-carboxylic acid, methyl ester was obtained and wastriturated with ethyl ether to a white solid; m.p. 162°-166° C.; α!_(D)=-106.0° (c=0.8, chloroform). TLC (ethyl acetate:hexanes, 6:4) R_(f)=0.36.

f) 4S-(4α,7α,10aβ)!-Decahydro-6-oxo-7-phthalimidopyrido 1,2-a!azepine,4-carboxylic acid, methyl ester

A solution of the title product from part (e) (1.068 g., 2.15 mmole) andtris(trimethylsilyl)silane (1.0 ml., 806 mg., 3.2 mmol.) in dry benzene(10 ml.) was heated to 50° C. and treated every 30 minutes with acatalytic amount (2-3 mg) of 2,2'-azobisisobutyronitrile. After 3.5hours, additional silane (400 μL) was added and the reaction wascontinued. After 5 hours, the slightly cloudy solution was cooled toroom temperature and concentrated. The residue was triturated with ethylether and the resulting solid was collected by filtration and washedthoroughly with ethyl ether affording 522 mg. of essentially pure titleproduct. The mother liquor was flash chromatographed (Merck silica gel,ethyl acetate:hexanes, 1:1) to give an additional 261 mg. of pureproduct for a total of 783 mg.; m. p. 179°-181° C.; α!_(D) =-10.6°(c=0.9, chloroform). TLC (ethyl acetate:hexanes, 1:1) R_(f) =0.25.

g) 4S- 4α,7α(R*),10aβ!-Decahydro-7-2-(acetylthio)-1-oxo-3-phenylpropyl!amino!-6-oxopyrido-1,2-a!azepine-4-carboxylic acid, methyl ester

The product from part (f) (786 mg., 2.12 mmole) in methanol (10 ml.) andmethylene chloride (2 ml.) was treated with hydrazine monohydrate (135μl, 2.8 mmol.) and the solution was stirred at room temperature for 66hours. The mixture was filtered and the solid was washed with methanol.The filtrate was stripped, triturated with methylene chloride, andfiltered again. The filtrate was washed with water and the aqueous layerwas back-extracted with methylene chloride. The pooled methylenechloride extracts were dried (sodium sulfate), filtered and stripped toafford 479 mg. of crude 4S-(4α,7α,10aβ)!-decahydro-7-amino-6-oxopyrido1,2-a!-azapine-4-carboxylic acid, methyl ester as a colorless oil. TLC(10% methanol in methylene chloride) R_(f) =0.18.

A cold (0° C.) solution of (S)-2-(acetylthio)benzenepropanoic acidobtained from the dicyclohexylamine salt as described previously, 524mg., 2.33 mmol.), triethylamine (295 μl., 214 mg., 2.11 mmol.) and theabove crude amine in methylene chloride (15 ml.) was treated withbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(940 mg., 2.12 mmol.). The solution was stirred at 0° C. for 1 hour andthen at room temperature for 2 hours. The solvent was stripped and theresidue was partitioned between ethyl acetate and 1N hydrochloric acid.The organic layer was washed successively with water, 50% saturatedsodium bicarbonate and brine, then dried (sodium sulfate), filtered andstripped. The residue was flash chromatographed (Merck silica gel, ethylacetate:hexanes, 1:1) to give 770 mg. of pure title compound as a whitefoam. TLC (ethyl acetate:hexanes) R_(f) =0.27.

h) 4S- 4α,7α(R*),10aβ!!-Decahydro-7-(2-mercapto-1-oxo-3-phenylproyl)amino!-6-oxopyrido1,2-a!azepine-4-carboxylic acid

A room temperature solution of the product from part (g) (755 mg., 1.70mmol.) in methanol (8 ml., deoxygenated via argon bubbling) was treatedwith 1N sodium hydroxide (10 ml., deoxygenated via argon bubbling).After stirring for 3 hours, the mixture was acidified with 10%hydrochloric acid, diluted with water and extracted with ethyl acetate.The ethyl acetate extract was washed with brine, then dried (sodiumsulfate), filtered and stripped. The residue was flash chromatographed(Merck silica gel, 1% acetic acid in ethyl acetate). The desired productfractions were stripped, azeotroped three times with ethyl acetate,taken up in a small amount of ethyl acetate and triturated with hexanes.The solvents were removed by rotary evaporation and the residue wasagain triturated with hexanes, stripped and dried in vacuo to afford 654mg. of title product as a white amorphous powder; α!_(D) =-31.0° (c=0.8,chloroform). TLC (2% acetic acid in ethyl acetate) R_(f) =0.51.

Anal. calc'd. for C₂₀ H₂₆ N₂ O₄ S.0.16 C₄ H₈ O₂.0.3 H₂ O: C, 60.46; H,6.85; N, 6.83; S, 7.82; Found: C, 60.57; H, 7.07; N, 6.57; S, 7.63.

EXAMPLE 36 3S- 3α(R*),7β!!-Hexahydro-3-(2-mercapto-2-oxo-3-phenylpropyl)amino!-2-oxo-7-(2-propenyl)-1H-azepine-1-aceticacid

a) (S)-N-(2-Phthalimido-1-oxohexyl)glycine, ethyl ester

A slurry of glycine, ethyl ester, hydrochloride salt (2.718 g, 19.5mmol.) in dimethylformamide (36 ml.) was treated with 4-methylmorpholine (2.60 ml., 2.39 g., 23.6 mmol.) and stirred at roomtemperature for 5 minutes. The mixture was then treated with(S)-2-phthalimido-6-hydroxyhexanoic acid (4.50 g., 16.2 mmol.) andhydroxybenzotriazole (2.225 g., 16.5 mmol.), cooled to 0° C., and thentreated with ethyl-3-(3-dimethylamino)propyl carbodiimide, hydrochloridesalt (3.438 g., 17.9 mmol.). After stirring at 0° C. for 1 hour and atroom temperature for 2 hours, the mixture was partitioned between ethylacetate and 0.5N hydrochloric acid and subsequently extracted threetimes with ethyl acetate. The pooled ethyl acetate extracts were washedin succession with water, saturated sodium bicarbonate, and brine, thendried (sodium sulfate), filtered and stripped to give 5.77 g. of titleproduct as a colorless oil. TLC (ethyl acetate) R_(f) =0.34.

b) (S)-N (2-Phthalimido-1,6-dioxohexyl)glycine, ethyl ester

A -78° C. solution of oxalyl chloride (1.67 ml., 2.43 g., 19.1 mmol.) inmethylene chloride (50 ml.) was treated dropwise with a solution of drydimethylsulfoxide (2.70 ml., 2.97 g., 38.0 mmol.) in methylene chloride(2 ml.). After 15 minutes, a solution of the product from part (a)(5.770 g., 15.9 mmol.) in methylene chloride (25 ml.) was added. Afteran additional 15 minutes, the mixture was treated with triethylamine(10.0 ml.), stirred at -78° C. for 5 minutes, then let warm to 0° C. Theresulting mixture was washed with 1N hydrochloric acid and brine, thendried (sodium sulfate), filtered and stripped. The residue was flashchromatographed (Merck silica gel, ethyl acetate:hexanes, 80:20) to give5.170 g. of title compound as a colorless oil.

c) (6S-trans)-Tetrahydro-6-phthalimido-oxazolo 3,2-b!azepine-2,5(3H,6H)-dione

A solution of the product from part (b) (5.16 g., 14.3 mmol.) intrifluoroacetic acid (40 ml.) and chloroform (160 ml.) was refluxedunder argon for 42 hours. The mixture was cooled to room temperature andneutralized with saturated aqueous sodium bicarbonate. The layers wereseparated and the aqueous layer was extracted with methylene chloride.The pooled organic layers were washed with brine, dried (sodiumsulfate), and filtered through a short plug of silica gel, washing with1:1-ethyl acetate:methylene chloride. The filtrate was stripped to givea solid residue. The residue was slurried in methylene chloride andtriturated with ethyl ether to give 3.437 g. of title product as a whitesolid. m.p. 234°-240° C. TLC (acetone:hexane, 1:1) R_(f) =0.51.

d)(3S-trans)-Hexahydro-3-phthalimido-2-oxo-7-(2-propenyl)-1H-azepine-1-aceticacid

A solution of the product from part (c) (2.6 g., 8.27 mmol.) andallyltrimethylsilane (10.0 ml., 7.19 g., 62.9 mmol.) in methylenechloride (75 ml.) at room temperature was treated with stannic bromide(1.0M in methylene chloride, 16.5 ml., 16.5 mmol.). After stirring atroom temperature for 9 hours and then at -20° C. for 14 hours, themixture was quenched with water and extracted with ethyl acetate/ethylether. The extract was washed with brine, dried (sodium sulfate),filtered and stripped to give a cloudy white oil. The oil was flashchromatographed (Merck silica gel, 2% acetic acid in ethyl acetate) togive 2.810 g. of the diastereomerically pure title compound as a whitefoam. TLC (5% acetic acid in ethyl acetate) R_(f) =0.55.

e)(3S-trans)-Hexahydro-3-phthalimido-2-oxo-7-(2-propenyl)-1H-azepine-1-aceticacid, methyl ester

A cold (0° C.) solution of the product from part (d) (2.50 g., 7.0mmol.) in methanol (20 ml.) and ethyl ether (30 ml.) was treated withexcess ethereal diazomethane for 10 minutes. The excess diazomethane wasdestroyed by the addition of acetic acid and the solvent was removed onthe rotary evaporator to give a yellow oil. The oil was flashchromatographed (Merck silica gel, 1:1-ethyl acetate:hexanes) to obtainthe product as a foam. The foam was dissolved in hot ethyl ethercontaining a little methylene chloride, cooled, and seeded to give 2.072g. of crystalline title product. The mother liquor yielded an additional262 mg. of product for a total of 2.334 g.; m. p. 107°-109° C. TLC(ethyl acetate:hexane, 1:1) R_(f) =0.29

f) 3S- 3α(R*),7β!!-Hexahydro-3-2-(acetylthio)-1-oxo-3-phenylpropyl!amino!-2-oxo-7-(2-propenyl)-1H-azepine-1-aceticacid, methyl ester

A slurry of the crystalline product from part (e) (492 mg., 1.33 mmol.)in methanol (10 ml.) was treated with hydrazine monohydrate (142 μl, 147mg., 2.93 mmol.) and the solution was briefly warmed to effectsolubilization of the starting material. After stirring at roomtemperature for 18 hours, the mixture was diluted with methylenechloride and filtered. The filtrate was stripped, slurried in methylenechloride, filtered and stripped again to give the crude amine (270 mg.,)as a colorless oil. A cold (0° C.) solution of the amine and(S)-2-(acetylthio)benzenepropanoic acid (obtained from thedicyclohexylamine salt as described previously, 287 mg., 1.28 mmol.) inmethylene chloride (12 ml.) was treated with triethylamine (172 μl., 125mg., 1.23 mmol.) followed bybenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(547 mg., 1.24 mmol.). The clear, nearly colorless solution was stirredat 0° C. for one hour and then at room temperature for 2 hours. Themixture was stripped, then partitioned between ethyl acetate and 1Nhydrochloric acid. The ethyl acetate extract was washed successivelywith water, 50% saturated sodium bicarbonate and brine. The solution wasdried (sodium sulfate), filtered and stripped. The residue was flashchromatographed (Merck silica gel, hexanes:acetone:ethyl ester, 6:3:1)to give 352 mg. of title product as an 84:16 mixture of diastereomers.This material was pooled with a similarly impure batch of product andthe combined material was purified by preparative reverse-phase highperformance liquid chromatography (YMC SH-365-10 S-10 120A ODS, 30×400mm column, isocratic 66% methanol/34% water, 50 ml/min, detecting at 220nm, title product t_(R) =22.6 min., impurity t_(R) =28.7 min.). Thetitle product was obtained as a colorless oil in 98.2% purity.TLC(acetone:hexanes, 4:6) R_(f) =0.38.

g) 3S- 3α(R*),7β!!-Hexahydro-3-(2-mercapto-1-oxo-3-phenylpropyl)amino!-2-oxo-7-(2-propenyl)-1H-azepine-1-aceticacid

A room temperature solution of the product from part (f) (720 mg., 1.61mmol.) in methanol (12 ml., deoxygenated via argon bubbling) was treatedwith 1N sodium hydroxide (10 ml., deoxygenated via argon bubbling).After stirring for 20 minutes, the solution was acidified with 10%hydrochloric acid (5 ml.) and extracted with ethyl acetate. The ethylacetate extract was washed with water and brine, then dried (sodiumsulfate), filtered and stripped to afford an oil. The material was flashchromatographed (Merck silica gel, 2-5% acetic acid in ethyl acetate).The product containing fractions were pooled and stripped, and theresidue was azeotroped three times with ethyl acetate. The resultingoil/foam was dissolved in a small amount of ethyl acetate and thentriturated with hexane to produce a white oil/foam. The mixture wasstripped to dryness, slurried in hexane, stripped to dryness again, anddried in vacuo to give 616 mg. of title product as a hard white foam;α!_(D) =-48.5° (c=0.63, chloroform). TLC (5% acetic acid in ethylacetate) R_(f) =0.56.

Anal.cal'd. for C₂₀ H₂₆ N₂ O₄ S.0.2 H₂ O: C, 60.95; H, 6.75; N, 7.11; S,8.14; Found: C, 60.98; H, 6.93; N, 6.93; S, 7.94

EXAMPLE 37 3S- 3α, (R*),7β!!-Hexahydro-3-(2-mercapto-1-oxo-3-phenylpropyl)amino!-2-oxo-7-propyl-1H-azepine-1-aceticacid

a) (3S-trans)-Hexahydro-3-phthalimido-2-oxo-7-propyl-1H-azepine-1-aceticacid, methyl ester

A solution of the product from Example 36(e) (767 mg., 2.07 mmol.) inmethanol (10 ml.) and ethyl acetate (10 ml.) was hydrogenated (balloon)over palladium (10% on carbon, 62 mg.) at room temperature for one hour.The mixture was filtered through Celite, stripped, redissolved in ethylacetate, filtered through a plug of silica gel and stripped again toafford 780 mg. of title product as a colorless oil. TLC (ethylacetate:hexanes, 1:1) R_(f) =0.29.

b) 3S- 3α(R*),7β!!-Hexahydro-3-2-(acetylthio)-1-oxo-3-phenylpropyl!amino!-2-oxo-7-propyl-1H-azepine-1-aceticacid, methyl ester

The product from part (a) (774 mg., 2.07 mmol.) in methanol (8 ml.) wastreated with hydrazine monohydrate (222 μl., 229 mg., 4.58 mmol.) andthe solution was stirred at room temperature for 23 hours. The mixturewas diluted with 0.5N hydrochloric acid (20 ml.)and stirred at 0° C. for2 hours. The solution was filtered and the filtrate was washed withethyl acetate. The ethyl acetate extract was back-extracted once withwater and the pooled aqueous layers were made basic with 1N sodiumhydroxide. Extraction with methylene chloride (three times) followed bydrying (sodium sulfate) and evaporation of the solvent afforded thecrude amine (354 mg.,) as a colorless oil.

A cold (0° C.) solution of this crude amine and(S)-(acetylthio)benzenepropanoic acid (obtained from thedicyclohexylamine salt as described previously, 344 mg., 1.53 mmol.) inmethylene chloride (12 ml.) was treated with triethylamine (214 μl., 154mg., 1.53 mmol.) followed bybenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(679 mg., 1.54 mmol.). The clear, nearly colorless solution was stirredat 0° C. for one hour and then at room temperature for one hour. Themixture was stripped, then partitioned between ethyl acetate and 0.5Nhydrochloric acid. The ethyl acetate extract was washed successivelywith water, 50% saturated sodium bicarbonate and brine. The solution wasdried (sodium sulfate), filtered and stripped. The residue was flashchromatographed (Merck silica gel, 6:4-hexanes:acetone) to give 510 mg.of pure title product as a colorless oil. TLC (acetone:hexanes, 4:6)R_(f) =0.31.

c) 3S- 3α(R*),7β!!-Hexahydro-3-(2-mercapto-1-oxo-3-phenylpropyl)amino!-2-oxo-7-propyl-1H-azepine-1-aceticacid

A room temperature solution of the product from part (b) (502 mg, 1.12mmol) in methanol (8 ml., deoxygenated via argon bubbling) was treatedwith 1N NaOH (6 mL, deoxygenated via argon bubbling). After stirring for25 minutes, the solution was acidified with 10% hydrochloric acid andextracted with ethyl acetate. The ethyl acetate extract was washed withwater and brine, then dried (sodiuum sulfate), filtered and stripped toafford an oil. The material was flash chromatographed (Merck silica gel,2% acetic acid in ethyl acetate). The product containing fractions werepooled and stripped, and the residue was azeotroped two times with ethylacetate. The resulting oil/foam was dissolved in a small amount ofmethylene chloride and then triturated with hexane to produce a whiteoil/foam. The mixture was stripped to dryness, slurried in hexane,stripped to dryness again, and dried in vacuo to give 394 mg. of titleproduct as a hard white foam; α!_(D) =-51.2° (c=0.65, chloroform). TLC(2% acedic acid in ethyl acetate) R_(f) =0.47.

Anal. calc'd. for C₂₀ H₂₈ N₂ O₄ S.0.2 H₂ O: C, 60.95; H, 6.75; N, 7.11;S, 8.14; Found: C, 60.98; H, 6.93; N, 6.93; S, 7.94.

EXAMPLE 38 3S- 3α(R*),7β!!-7-(Cyclopropylmethyl)hexahydro-3-(2-mercapto-1-oxo-3-phenylpropyl)amino!-2-oxo-1H-azepine-1-acetic acid

a)(3S-trans-7-(Cyclopropylmethyl)hexahydro-3-phthalimido-2-oxo-1H-azepine-1-aceticacid, methyl ester

To a solution of the product from Example 36(e) (700 mg. 1.89 mmol.) in5 ml. of methylene chloride, cooled to 0° C., was added a 75 ml. portionof diazomethane/ethyl ether solution (prepared according to theprocedure of Fieser & Fieser, Vol. I, p. 192), followed by 7 mg. (0.03mmol.) of palladium(II) acetate. The reaction mixture bubbled violentlyand turned clear. After stirring for 10 minutes an additional 25 ml. ofdiazomethane/ethyl ether solution was added to the reaction. Thereaction was stirred at 0° C. for 50 minutes, then filtered throughcelite and concentrated in vacuo to give a crude oil. The crude oil wasflash chromatographed (Merck silica, 50×150 mm, 1:2 ethylacetate/hexane) to give 717 mg. of title product as a white foam.

b) 3S- 3α(R*),7β!!-7-(Cyclopropylmethyl)hexahydro-3-2-(acetylthio)-1-oxo-3-phenylpropyl!amino!-2-oxo-1H-azepine-1-aceticacid, methyl ester

To a solution of the product from part (a) (697 mg., 1.81 mmol.) in 8ml. of methanol, stirred at room temperature, was added dropwise 92 μL(1.90 mmol.) of hydrazine monohydrate. The reaction was stirred at roomtemperature for 48 hours, then filtered to remove the solid byproducts.The filtrate was concentrated in vacuo, dissolved in methylene chloride,refiltered and reconcentrated to give a crude oil. The crude oil wasdried under vacuum to give 441 mg. of crude amine as a white foam. Thiscrude foam was used in the next reaction without further purification.

To a cold (0° C.) solution of 420 mg.(1.64 mmol.) of this crude amineand 384 mg. (1.81 mmol. of (S)-2-(acetylthio)benzenepropanoic acid(obtained from the dicyclohexylamine salt as described previously) in 10ml. of chloroform was added 280 μl. (1.97 mmol.) of triethylamine. Thereaction mixture was stirred 30 minutes, then 799 mg. (1.81 mmol.) ofbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphatewas added. The reaction was stirred at 0° C. for 48 hours, then anadditional 399 mg. (0.904 mmol.) ofbenzotriazol-1-yloxytris(dimethylamino)phoisphonium hexafluorophosphateand 4 drops of triethylamine were added. The reaction was stirred at 0°C. for an additional 24 hours, then partitioned between 50 ml. ethylacetate/50 ml. 5% potassium bisulfate solution. The water layer wasseparated and extracted with 2-25 ml. portions of ethyl acetate; thecombined ethyl acetate layers were washed with 25 ml. of 5% potassiumbisulfate solution, 40 ml. saturated sodium bicarbonate, 40 ml. brine,dried (magnesium sulfate) and concentrated in vacuo to give a crude oil.The oil was flash chromatographed (Merck silica gel, 50×200 mm, 1:3ethyl acetate/hexane, then 1:2 ethyl acetate/hexane) to give 678 mg. oftitle product as a white foam.

c) 3S- 3α(R*),7β!!-7-(Cyclopropylmethyl)hexahydro-3-(2-mercapto-1-oxo-3-phenylpropyl)amino!-2-oxo-1H-azepine-1-acetic acid.

A solution of 658 mg. (1.43 mmol.) of the product from part (b) in 10ml. of methanol was purged with argon for 30 minutes and cooled to 0° C.To this solution was added dropwise 6 ml. of 1M sodium hydroxide, alsopurged with argon for 30 minutes and cooled to 0° C. The reaction wasstirred at 0° C. for 1 hour with continuous argon purging, thenacidified to pH 1 with 5% potassium bisulfate solution. The mixture wasextracted with 3-80 ml. portions of ethyl acetate; the combined ethylacetate layers were dried (magnesium sulfate) and concentrated in vacuoto give a crude oil. The oil was flash chromatographed (Merck silicagel, 50×150 mm, 0.2% acetic acid/ethyl acetate) to give a white foam.The foam was triturated from methylene chloride/hexane to give 490 mg.of title product as a white hard solid; α!_(D) =-78.9° (c=1.0, CDCl₃).TLC (5% methanol in methylene chloride plus 3 drops acetic acid) R_(f)=0.41.

Anal.calc'd. for C₂₁ H₂₈ N₂ SO₄.0.50 H₂ O: C, 61.00; H, 7.07; N, 6.77;S, 7.93; Found: C, 61.40; H, 6.75; N, 6.37; S, 7.75.

EXAMPLE 39 3S- 3α(R*),7β!!-7-(Cyclopentyl)hexahydro-3-(2-mercapto-1-oxo-3-phenylpropyl)amino!-2-oxo-1H-azepine-1-acetic acid

a)(3S-trans)-7-(2-Cyclopentenyl)hexahydro-3-phthalimido-2-oxo-1H-azepine-1-aceticacid, methyl ester

Tin tetrachloride (5.1 ml., 5.1 mmol., 1M methylene chloride) was addeddropwise to a solution of the product from Example 36 (e) (800 mg., 2.55mmol.) and (2-cyclopentenyl)trimethylsilane (2.85 g., 20.4 mmole) inmethylene chloride (60 ml.). The mixture was stirred at room temperaturefor 18 hours, then quenched by the addition of 100 ml. of water. Themixture was extracted with 3-100 ml. portions of ethyl acetate and 2-100ml. portions of ethyl ether; the combined organic layers were washedwith 100 ml. of brine, dried (sodium sulfate) and concentrated in vacuoto give a crude oil. The oil was flash chromatographed (Merck silicagel, 50×100 mm, 1:1 ethyl acetate/hexane then 2% acetic acid/ethylacetate) to give 788 mg. of(3S-trans)-7-(2-cyclopentenyl)hexahydro-3-phthalimido-2-oxo-1H-azepine-1-aceticacid as a white foam.

A solution of this acid (768 mg., 2.01 mmol.) in methanol (7 ml.)/ethylether (10 ml.) stirred at room temperature, was treated dropwise with asolution of diazomethane/ethyl ether (prepared according to theprocedure of Fieser & Fieser, Vol. I, p. 192). The diazomethane/ethylether solution was added until the reaction mixture remained yellow andthe bubbling ceased. The mixture was stirred 10 minutes, then the excessdiazomethane was quenched by the dropwise addition of 0.3 ml. of aceticacid. The colorless solution was concentrated in vacuo to give a crudeoil. The oil was flash chromatographed (Merck silica gel, 50×100 mm, 1:2ethyl acetate/hexane) to give 640 mg. of title product as a white foam.

b)(3S-trans)-7-(Cyclopentyl)hexahydro-3-phthalimido-2-oxo-1H-azepine-1-aceticacid, methyl ester

A solution of the product from part (a) (700 mg., 1.89 mmol.) in 5 ml.of methanol was purged with argon for 15 minutes, then 150 mg. (25% byweight) of 10% palladium on carbon was added. The reaction vessel wasevacuated and filled with hydrogen three times and stirred underhydrogen (1 atm, balloon) for 5 hours. The reaction mixture was filteredthrough Celite; the filtrate was concentrated in vacuo to give 594 mg.of title product as a white foam.

c) 3S- 3α(R*),7β!!-7-(Cyclopentyl)hexahydro-3-2-(acetylthio)-1-oxo-3-phenylpropyl!amino!-2-oxo-1H-azepine-1-aceticacid, methyl ester

A solution of the product from part (b) in methanol was treated withhydrazine monohydrate according to the procedure described in Example 38part (b) affording crude(3S-trans)-7-(cyclopentyl)hexahydro-3-amino-2-oxo-1H-azepine-1-aceticacid, methyl ester as a white foam.

This white foam was treated with (S)-(acetylthio)benzenepropanoic acidaccording to the procedure described in Example 38 part (b) affordingthe title product as a clear oil.

d) 3S- 3α(R*),7β!!-7-(Cyclopentyl)hexahydro-3-(2-mercapto-1-oxo-3-phenylpropyl)amino!-2-oxo-1H-azepine-1-acetic acid

A solution of the product from part (c) in methanol was treated with 1Msodium hydroxide according to the procedure of Example 38 part (c)affording the title product as a white hard solid; α!_(D) =-78.1° (c=1,CDCl₃). TLC (5% methanol in methylene chloride plus 3 drops acetic acid)R_(f) =0.39.

Anal. Calc'd. for C₂₂ H₃₀ N₂ SO₄.0.03 H₂ O: C, 63.06; H, 7.23; N, 6.69;S, 7.65; Found: C, 63.25; H, 7.25; N, 6.50; S, 7.55.

EXAMPLE 40 S-(R*,R*)!-Hexahydro-3-(2-mercapto-1-oxo-3-phenylpropyl)amino!-2-oxo-1H-azepine-1-propanoicacid

a) (S)-3-(1,1-Dimethylethoxy)carbonyl!amino!-hexahydro-2-oxo-1H-azepine-1-propanoicacid, ethylester

A solution of the product from Example 9(b) (1.75 g., 7.67 mmol.) intetrahydrofuran:t-butanol (2:1, 30 ml.) was cooled to 0° C. and treatedwith ethyl acrylate (1.16 ml., 10.74 mmol., 1.4 eq.) and then 1.0Nt-butanol, potassium salt (767 μl., 0.1 eq.). The reaction mixture wasstirred at 0° C. for 15 minutes then at room temperature for 1 hour. Thereaction was quenched with 25% ammonium chloride (50 ml.) and extractedwith ethyl acetate (2×125 ml.). The combined organics was washed with25% ammonium chloride (50 ml.), water (100 ml.), and brine (100 ml.),dried over magnesium sulfate, filtered and concentrated to yield a clearsyrup. The residue was purified by chromatography on a 5×15 cm silicagel column eluting with 30% ethyl acetate/hexane mixture. The desiredfractions were combined and concentrated to afford 2.18 g. title productas a clear syrup. TLC (ethyl acetate:hexane, 1:1) R_(f) =0.38.

b) S-(R*,R*)!-Hexahydro-3-2-(acetylthio)-1-oxo-3-phenylpropyl!amino!-2-oxo-1-azepine-1-propanoicacid, ethyl ester

The product from part (a) (2.15 g., 6.55 mmole) was treated with 4Nhydrochloric acid/dioxane (30 ml., 120 mmole) at 0° C. for 30 minutes,then at room temperature for 2 hours. The reaction mixture wasconcentrated, stripped with ethyl ether (twice), azeotroped with toluene(3 times) and dried in vacuo for 5 hours affording(S)-3-amino-hexahydro-2-oxo-1H-azepine-1-propanoic acid, ethyl ester,hydrochloride salt.

This amine was them coupled with (S)-(acetylthio)benzenepropanoic acidin the presence of triethylamine andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphateas described in Example 31 part (c) affording the title product. TLC(ethyl acetate:hexane, 1:1) R_(f) =0.19.

c) S-(R*,R*)-Hexahydro-3-(2-mercapto-1-oxo-3-phenylpropyl)amino!-2-oxo-1H-azepine-1-propanoicacid

The product from part (b) in methanol was treated with 1N sodiumhydroxide as described in Example 31 part (d) affording the titleproduct as a white foam; α!_(D) =+4.44° (c=1.24, methanol). TLC (1%acetic acid in ethyl acetate) R_(f) =0.27.

Anal. calc'd. for C₁₈ H₂₄ N₂ O₄ S.0.17 H₂ O: C, 58.83; H, 6.67; N, 7.62;S, 8.72; Found: C, 58.83; H, 6.87; N, 7.33; S, 8.49.

EXAMPLE 41 S-(R*,R*)!-Hexahydro-3-(2-mercapto-1-oxo-3-phenylpropyl)amino!-2-oxo-.alpha.-(phenylmethyl)-1H-azepine-1-aceticacid

a) (R*)-N-(2-Phthalimido-6-hydroxy-1-oxohexyl)-L-phennylalanine, ethylester

To a solution of L-phenylalanine, ethyl ester, hydrochloride salt (998mg., 4.3 mmol.) in dimethylformamide (10 ml.) was added4-methylmorpholine (575 μl., 529 mg, 5.2 mmol). After stirring at roomtemperature for 5 minutes, the solution was cooled to 0° C. and treatedsuccessively with (S)-2-phthalamido-6-hydroxyhexanoic acid (1.002 g.,3.6 mmol.), hydroxybenzotriazole (582 mg., 4.3 mmol.), andethyl-3-(3-dimethylamino)propyl carbodiimide, hydrochloride salt (770mg., 4.0 mmol.). The resulting mixture was stirred at 0° C. for 0.5 hourand at room temperature for 1.5 hours. The solution was partitionedbetween ethyl acetate and water and the organic extract was washedsuccessively with 0.5N hydrochloric acid, water, 50% saturated sodiumbicarbonate, and brine, then dried (sodium sulfate), filtered andstripped to give 1.63 g. of essentially pure title product as anoil/foam. TLC (acetone:hexanes, 1:1) R_(f) =0.30.

b) (R*)-N-(2-Phthalimido-1,6-dioxohexyl)-L-phenylalanine, ethyl ester

A -78° C. solution of oxalyl chloride (370 μl., 538 mg., 4.2 mmol.) inmethylene chloride (10 ml.) was treated dropwise with a solution of drydimethylsulfoxide (610 μl., 672 mg., 8.6 mmol.) in methylene chloride(1.5 ml.). After 10 minutes, a solution of the product from part (a)(1.616 g., 3.6 mmol.) in methylene chloride (10 ml.) was added. After anadditional 15 minutes, the mixture was treated with triethylamine (4.0ml.), stirred at -78° C. for 5 minutes, then let warm to 0° C. Theresulting white slurry was partitioned between 0.5N hydrochloric acidand ethyl acetate. The organic extract was washed with brine, then dried(sodium sulfate), filtered and stripped. The residue was flashchromatographed (Merck silica gel, 40:60-acetone:hexanes) to afford1.474 g.of title product as an oil/foam. TLC (acetone:hexanes, 1:1)R_(f) =0.45.

c) 3S-(3α,6β,9aα)!-Tetrahydro-3-(phenylmethyl)-6-phthalimido-oxazole3,2-a!azepine-2,5(3H,6H)-dione

A mixture of the product from part (b) (6.11 g., 13.6 mmol.) andtrifluoroacetic acid (34 ml.) in chloroform (205 ml.) was refluxed for 6days. The solution was cooled to room temperature and neutralized withsaturated sodium bicarbonate. The layers were separated and the aqueouslayer was extracted with methylene chloride. The pooled organic layerswere washed with water, dried (sodium sulfate), filtered and stripped togive a dark yellow-orange oil. The residue was flash chromatographed(Merck silica gel, 40 to 60% ethyl acetate in hexanes) to afford 3.075g. of title product as a white foam.

d)S-(R*,R*)!-Hexahydro-2-oxo-3-phthalimido-α-(phenylmethyl)-1H-azepine-1-aceticacid, methyl ester

A solution of the product from part (c) (1.40 g., 3.46 mmol.) andtriethylsilane (4.4 ml., 3.20 g., 27.5 mmol.) in methylene chloride (42ml.) at room temperature was treated dropwise with titaniumtetrachloride (1.0M in methylene chloride, 7.0 ml., 7.0 mmol.). Theclear colorless solution became bright yellow upon the addition oftitanium tetrachloride; no precipitate resulted. After stirring for 66hours, the mixture was quenched with water and extracted with ethylacetate. The ethyl acetate extract was washed with water and brine,dried (sodium sulfate), filtered and stripped to give an oil. Flashchromatography (Merck silica gel, ethyl acetate followed by 2% aceticacid in ethyl acetate) provided 870 mg. ofS-(R*,R*)!-hexahydro-2-oxo-3-phthalimido-α-(phenylmethyl)-1H-azepine-1-aceticacid as a white foam.

A cold (0° C.) solution of this acid (898 mg., 2.21 mmol.) in methanol(8 ml.) and methylene chloride (12 ml.) was treated with excess etherealdiazomethane for 5 minutes. The excess diazomethane was destroyed by theaddition of acetic acid and the solvent was removed on the rotaryevaporator to give a yellow oil. The residue was flash chromatographed(Merck silica gel, 50 to 60% ethyl acetate in hexanes) affording 858 mg.of title product as a white foam. TLC (ethyl acetate:hexanes, 1:1) R_(f)=0.30.

e) S-(R*,R*)!-Hexahydro-3-2-(acetylthio)-1-oxo-3-phenylpropyl!amino!-2-oxo-α-(phenylmethyl)-1H-azepine-1-aceticacid, methyl ester

A solution of the product from part (d) in methanol was treated withhydrazine monohydrate according to the procedure of Example 36 part (f)affordingS-(R*,R*)!-hexahydro-3-amino-2-oxo-α-(phenylmethyl)-1H-azepine-1-aceticacid, methyl ester as a pale yellow oil. TLC (methylene chloride:aceticacid:methanol, 8:1:1) R_(f) =0.60.

A cold (0° C.) solution of this amine was reacted with(S)-2-(acetylthio)benzenepropanoic acid in the presence of triethylamineand benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate according to the procedure of Example 36 (f)affording the title product as a colorless oil/foam. TLC(acetone:hexanes, 1:1) R_(f) =0.54.

f) S-(R*,R*)!-Hexahydro-3-(2-mercapto-1-oxo-3-phenylpropyl)amino!-2-oxo-.alpha.-(phenylmethyl)-1H-azepine-1-aceticacid

A solution of the product from part (e) in methanol was treated with 1Nsodium hydroxide according to the procedure of Example 36 part (g)affording the title product as a relatively hard white foam; α!_(D)=-64.2° (c=0.54, chloroform). TLC (5% acetic acid in ethyl acetate)R_(f) =0.60.

Anal.calc'd. for C₂₄ H₂₈ N₂ O₄ S.0.31 H₂ O: C, 64.61; H, 6.47; N, 6.28;S, 7.19; Found: C, 64.61; H, 6.78; N, 5.89; S, 7.46

EXAMPLE 42 6(S)!-Hexahydro-6-(2-mercapto-1-oxo-3-phenyl-propyl)amino!-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid

a) 2,2-Dimethylcyclohexanone, oxime

A solution of 2,2-dimethylcyclohexanone (8.960 g., 65 mmol.), pyridine(12.0 ml., 12.27 g., 155 mmol.), and hydroxylamine hydrochloride (10.30g., 148 mmol.) in absolute ethanol (50 ml.) was heated at 85° C. for 2hours. The cooled mixture was partitioned between ethyl ether and waterand the ethereal layer was washed successively with 1N hydrochloric acidand brine, then dried (sodium sulfate), filtered and stripped. The solidresidue was dissolved in a small amount of hot hexane and cooled to 0°C. to afford 6.801 g. of title product as white flakes; m. p. 91°-93° C.TLC (ethyl acetate:hexane, 4:6) R_(f) =0.60.

b) Hexahydro-3,3-dichloro-7,7-dimethyl-2-oxo-2H-azepine

A cold (0°-10° C.) slurry of phosphorus pentachloride (32.50 g., 156.1mmol.) in methylene chloride (250 ml.) was treated with a solution ofthe product from part (a) (7.353 g., 52.1 mmol.) in methylene chloride(50 ml.) over a 10 minute period. The mixture was warmed to roomtemperature and chlorine gas was bubbled through the solution at 0.5 and1.5 hours after addition of the oxime. After a total of 3 hours, themixture was quenched with crushed ice (70 ml.) followed by saturatedsodium bicarbonate (150 ml.). Periodic cooling was necessary. Thebiphasic mixture was stirred vigorously at room temperature for 18hours, then the layers were separated and the methylene chloride extractwas washed with saturated sodium bicarbonate/brine. The organic layerwas dried (sodium sulfate), filtered, stripped, and flashchromatographed (Merck silica gel, 2/8-ethyl acetate/methylenechloride). Fractions containing the desired product were stripped andthe residue was dissolved in hot methylene chloride/ethyl acetate andcooled to afford 5.152 g. of pure title product. The mother liquor wasre-chromatographed (Merck silica gel, 1/9-ethyl acetate/methylenechloride) to give an additional 2.054 g. of pure product for a totalyield of 7.206 g.; m. p. 148°-155° C. (broad). TLC (ethylacetate:methylene chloride, 1:9) R_(f) =0.36.

c) Hexahydro-3-chloro-7,7-dimethyl-2H-azepine

A solution of the product from part (b) (7.180 g., 34.2 mmol.) inglacial acetic acid (150 ml.) was hydrogenated (balloon) over 10%palladium on carbon catalyst (2.5 g.) for 1.75 hours. The mixture wasfiltered through Celite and the solvent was removed by rotaryevaporation. The residue was flash chromatographed (Merck silica gel,3/7-ethyl acetate/methylene chloride) to afford impure desired productas an oily solid. The residue was treated with ethyl ether andtriturated with hexane to afford 2.845 g. of pure title product as awhite solid. The mother liquor was re-chromatographed (Merck silica gel,3/7-ethyl acetate/methylene chloride) to give 1.93 g. of additional puresolid product. The solids were pooled to give 4.775 g.of pure titleproduct; m. p. 115°-117° C. TLC (ethyl acetate:methylene chloride, 3:7)R_(f) =0.41.

d) Hexahydro-3-azido-7,7-dimethyl-2-oxo-2H-azepine

A slurry of the product from part (c) (4.670 g., 26.6 mmol.) and sodiumazide (4.360 g., 67.0 mmol.) in dry dimethylsulfoxide (100 ml.) washeated at 80° C. for 6 hours. The solution was cooled to 0° C. andtreated with 175 ml. of ice cold water. The resulting snow whiteprecipitate was collected by filtration, washed with water and dried togive 2.37 g. of pure title product. The filtrate was extracted withethyl acetate and the organic extract was washed twice with water andonce with brine, then dried (sodium sulfate), filtered and stripped.Trituration of the residue with ethyl ether and hexane afforded 1.637 g.of additional product. The isolated solids were pooled to give 4.007 g.of pure title product; m. p. 98°-100° C. TLC (ethyl acetate:hexane,75:25) R_(f) =0.51.

e) Hexahydro-3-(1,1-dimethylethoxy)carbonyl!-amino!-7,7-dimethyl-2-oxo-2H-azepine

A solution of the product from part (d) (3.469 g., 19.0 mmol.) inmethanol (80 ml.) was hydrogenated (balloon) over 10% palladium oncarbon catalyst (850 mg.) for 1.5 hours. The mixture was filteredthrough Celite and the solvent was removed by rotary evaporation. Theresidue was evaporated once from methylene chloride to afford the crudeamine as a white solid. The solid was redissolved in chloroform andtreated successively with triethylamine (2.65 ml., 1.92 g., 19.0 mmol.)and ditert-butyl-dicarbonate (5.000 g., 22.9 mmol.). After stirring atroom temperature for 1 hour, the solution was stripped and the residuewas triturated with ethyl acetate/ethyl ether to afford 2.668 g. oftitle product as a white solid. The filtrate was flash chromatographed(Merck silica gel, 2/8-ethyl acetate/methylene chloride) to giveadditional pure product which was pooled with the above solid to give atotal of 4.082 g. of pure title product; m. p. 156°-158.5° C. TLC (ethylacetate:methylene chloride, 2:8) R_(f) =0.26.

f) Hexahydro-3-(1,1-dimethylethoxy)carbonyl!-amino!-7,7-dimethyl-2-oxo-1H-azepine-1-aceticacid, ethyl ester

A room temperature solution of the product from part (e) (3.512 g., 13.7mmol.) in dry tetrahydrofuran (110 ml.) was treated with lithiumhexamethyldisilazane (1.0M in tetrahydrofuran, 21 ml., 21 mmol.)followed by ethyl bromoacetate (3.0 ml., 4.52 g., 27.0 mmol.). After 20minutes, additional lithium hexamethyldisilazane (21 ml.) was addedfollowed by an additional 1.5 ml. of ethyl bromoacetate. The dark orangesolution was stirred at room temperature for an additional 30 minutes,then quenched by the addition of saturated ammonium chloride and water.The mixture was extracted with ethyl acetate and the organic extract waswashed with brine, dried (sodium sulfate), filtered, and stripped togive a dark oil. The residue was flash chromatographed (Merck silicagel, 35 to 50% ethyl acetate in hexane) to give 1.363 g. of pure titleproduct as a pale yellow oil. TLC (ethyl acetate:hexane, 1:1) R_(f)=0.48.

g) 6(S)!-Hexahydro-6-2-(Acetylthio)-1-oxo-3-phenylpropyl!amino!-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid, ethyl ester

A solution of the product from part (f) (1.349 g., 3.94 mmol.) inp-dioxane (3 ml.) was treated with hydrochloric acid (4.0M in p-dioxane,12 ml.). The mixture was stirred at room temperature for 1.5 hours. Thesolvent was stripped and the residue was partioned between methylenechloride and 0.2N sodium hydroxide (26 ml.). The layers were separatedand the aqueous layer was extracted with ethyl ether/ethyl acetate. Thepooled organic extracts were dried (sodium sulfate), filtered andstripped to give 982 mg. of the crude free amine as a yellow oil. TLC(methanol:methylene chloride, 1:9) R_(f) =0.16.

A solution of (S)-2-(acetylthio) benzene-propanoic acid obtained fromthe dicyclohexylamine salt as previously described (973 mg., 4.3 mmol.)!and the above crude amine in methylene chloride (30 ml.) was treatedwith triethylamine (1.15 ml., 835 mg., 8.2 mmol.) and the mixture wascooled to 0° C. Benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate (1.915 g., 4.3 mmol.) was then added as a solid. Thesolution was stirred at 0° C. for 1 hour and then at room temperaturefor 1.5 hours. The solvent was stripped and the residue was partitionedbetween ethyl acetate and 0.5N hydrochloric acid. The organic layer waswashed successively with water, 50% saturated sodium bicarbonate andbrine, then dried (sodium sulfate), filtered and stripped. The residuewas flash chromatographed (Merck silica gel, 3:7 acetone:hexanes) togive 1.564 g. of title product as an oil. (1:1 mixture ofdiastereomers). TLC (acetone:hexanes, 3:7) R_(f) =0.30.

h) 6(S)!-Hexahydro-6-(2-mercapto-1-oxo-3-phenylpropyl)amino!-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid

A room temperature solution of the product from part (g) (1.548 g., 3.45mmol.) in methanol (20 ml., deoxygenated via argon bubbling) was treatedwith 1N sodium hydroxide (15 ml., deoxygenated via argon bubbling).After stirring for 30 minutes, additional 1N sodium hydroxide (15 ml.)was added and stirring under argon continued. After a total of 3 hours,the solution was acidified with 6N hydrochloric acid and extracted withethyl acetate. The ethyl acetate extract was washed with water andbrine, then dried (sodium sulfate), filtered and stripped to afford anoil. The material was flash chromatographed (Merck silica gel, ethylacetate followed by 1.5% acetic acid in ethyl acetate). The fractionscontaining essentially pure title product were pooled, stripped, andazeotroped twice with ethyl acetate. The mixture was dissolved in asmall amount of ethyl acetate and triturated with hexane to give a foam.The volatiles were stripped, the residue was slurried in hexane,stripped to dryness again, and dried in vacuo to give 863 mg. of titleproduct as a relatively hard white foam as a 45:55 mixture ofdiastereomers. TLC (2% acetic acid in ethyl acetate) R_(f) =0.40.

Anal. calc'd. for C₁₉ H₂₆ N₂ O₄ S.0.2 H₂ O: C, 59.73; H, 6.96; N, 7.33;S, 8.39; Found: C, 59.79; H, 7.13; N, 7.13; S, 7.99.

EXAMPLE 43 S-(R*,S*)!-3,4-Dihydro-3-(2-mercapto-1-oxo-3-phenylpropyl)amino!-4-oxo-1,5-benzothiazepine-5(2H)-propanoicacid

a) 2,3-Dihydro-3-amino-4-oxo-1,5-benzothiazepine-5(4H)-propanoic acid,ethyl ester

2,3-Dihydro-3-(phenylmethoxy)carbonyl!-amino!-1,5-benzothiazepine-4(5H)-one preparedaccording to the procedure of Slade et al., J. Med. Chem., 28, p1517-1521 (1985)! (2.04 g., 6.21 mmol.) was azeotroped with a mixture ofmethylene chloride/toluene (3×) and dried in vacuo for one hour. Asuspension of this compound in tetrahydrofuran:tert-butanol (2:1, 21ml.), cooled to 0° C., was treated with ethyl acrylate (1.08 ml., 9.94mmol., 1.6 eq.) and then 1.0N t-butanol, potassiun salt/tetrahydrofuran(621 μl., 0.1 eq.). The reaction mixture was stirred at 0° C. for 15minutes then at room temperature for 20 hours under argon. The reactionwas quenched with 50% ammonium chloride (50 ml.) and extracted withethyl acetate (2×150 ml.). The combined organics were washed withsaturated ammonium chloride (75 ml.), water (75 ml.), and brine (100ml.), dried over magnesium sulfate, filtered and concentrated to yield aclear yellow syrup. The residue was purified by chromatography on a 5×20cm silica gel column eluting with 20% ethyl acetate/hexane mixture (2l.). The desired fractions were combined and concentrated to afford 2.33g of a mixture of 2,3-dihydro-3- (3-ethoxy-3-oxopropyl)-(phenylmethoxy)carbonyl!amino!-4-oxo-1,5-benzothiazepine-5(4H)-propanoicacid, ethyl ester (25%) and 2,3-dihydro-3-(phenylmethoxy)carbonyl!-amino!-4-oxo-1,5-benzothiazepine-5(4H)-propanoicacid, ethyl ester (75%) as a clear syrup.

The above mixture (698 mg., 1.32 mmol. of the first named compound and1.698 g., 3.96 mmol. of the second named compound) and 30% hydrogenbromide/acetic acid solution (8.71 ml., 41.98 mmol.) was stirred underargon at room temperature for 1.5 hours. The reaction mixture wasdiluted with ethyl ether (200 ml.), stirred until off-white precipitatesformed and filtered, washing the orange solids with ethyl ether (4×50ml.). The crude residue was then dissolved in 1N hydrochloric acid (100ml.) and extracted with ethyl acetate (2×100 ml.). The aqueous phase wasthen brought to pH 9 with 1N sodium hydroxide and extracted with ethylacetate (3×100 ml.). The combined organics were washed with brine (75ml.), dried over magnesium sulfate, filtered and concentrated to yield1.50 g. crude yellow oil. The residue was purified by chromatography ona 5×20 cm silica gel column eluting with 1% (2 l.), 2% (1 l.), andfinally 5% (1 l.) of methanol in methylene chloride. The desiredfractions were concentrated and dried in vacuo to yield 1.163 g. oftitle product. TLC (methylene chloride:methanol, 9:1) R_(f) =0.40.

b) S-(R*,S*)!-3,4-Dihydro-3-2-(acetylthio)-1-oxo-3-phenylpropyl!amino!-4-oxo-1,5-benzothiazepine-5(2H)-propanoicacid, ethyl ester

(S)-2-(Acetylthio)benzenepropanoic acid (obtained from thedicyclohexylamine salt as previously described) was dissolved in drymethylene chloride, cooled to 0° C., and treated with a solution of theproduct from part (a) in dry methylene chloride followed bytriethylamine and benzotriazol-1-yloxy(dimethylamino)phosophoniumhexafluorophosphate as described in Example 36 part (f) affording thetitle product. TLC (ethyl acetate:hexane, 1:1) R_(f) =0.39.

c) S-(R*,R*)!-3,4-Dihydro-3-(2-mercapto-1-oxo-3-phenylpropyl)amino!-1,5-benzothiazepine-5(2H)-propanoicacid

A solution of the product from part (b) in methanol was treated with 1Nsodium hydroxide according to the procedure of Example 36 part (g)affording the title product as a white foam; α!_(D) =-161.6° (c=1.16,methanol). TLC (1% acetic acid in ethyl acetate) R_(f) =0.45.

Anal. calc'd. for C₂₁ H₂₂ N₂ O₄ S₂.0.4 H₂ O: C, 57.63; H, 5.25; N, 6.40;S, 14.65; Found: C, 57.65; H, 5.04; N, 6.38; S, 14.44.

EXAMPLE 44 3(S)!-2,3,4,5-Tetrahydro-3-(2-mercapto-1-oxo-3-phenylpropyl)amino!-2-oxo-1H-1-benzazepine-1-propanoicacid

a) 3-Amino-2,3,4,5-Tetrahydro-2-oxo-1H-1-benzazepine-1-propanoic acid,ethyl ester

A solution of 3-azido-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one preparedas described by Watthey et al., J. Med. Chem., 28, p. 1511-15156 (1985)!in tetrahydrofuran/tert-butanol was cooled to 0° C. and treated withethyl acrylate and 1N tert-butanol, potassium salt/tetrahydrofuranaccording to the procedure of Example 40 part (a) affording3-azido-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-propanoic acid,ethyl ester as a syrup. TLC (ethyl ether:hexane, 1:1) R_(f) =0.45.

A solution of this compound (2.258 g., 6.94 mmol.) in absolute ethanolwas treated with 10% palladium on carbon catalyst and hydrogenated at 40psi for 4 hours, venting the Parr bottle after the first hour. Themixture was diluted with ethanol (50 ml.) and filtered through a Celitepad, washing the pad thoroughly with ethanol (2×50 ml.). The clearfiltrate was evaporated to dryness and dried in vacuo to give 2.098 g.of the title product as a clear light yellow syrup. TLC (methylenechloride:methanol, 9:1) R_(f) =0.32.

b) 3(S)!-2,3,4,5-Tetrahydro-3-2-(acetylthio)-1-oxo-3-phenylpropyl!amino!-2-oxo-1H-1-benzazepine-1-propanoicacid

(S)-2-(Acetylthio)benzenepropanoic acid obtained from thedicyclohexylamine salt as previously described! was dissolved inmethylene chloride, cooled down to 0° C., and treated sequentially witha solution of the product from part (a) in dry methylene chloride,triethylamine, and benzotriazol-1-yloxytris (dimethylamino)phosphoniumhexafluorophosphate according to the procedure of Example 36 part (f)affording the title product as a syrup. TLC (ethyl acetate:hexane, 1:1)R_(f) =0.56 and 0.52.

c) 3(S)!-2,3,4,5-Tetrahydro-3-(2-mercapto-1-oxo-3-phenylpropyl)amino!-2-oxo-1H-1-benzazepine-1-propanoicacid

A solution of the product from part (b) in methanol was cooled down to0° C. and treated with 1N sodium hydroxide according to the procedure ofExample 36 part (g) affording the title product as a solid foam; α!_(D)=+41.8° (c=0.608, methanol). TLC (methylene chloride:methanol:aceticacid, 20:1:1) R_(f) =0.47.

Anal. calc'd.for C₂₂ H₂₄ N₂ O₄ S.0.25 C₅ H₁₂.0.413 H₂ O: C, 63.76; H,6.21; N, 6.40; S, 7.32; Found: C, 63.76; H, 6.18; N, 6.38; S, 7.45.

EXAMPLE 45 3(S)!-2,3,4,5-Tetrahydro-3-2-(mercaptomethyl)-1-oxo-3-phenylpropyl!amino!-2-oxo-1H-1-benzazepine-1-propanoicacid

a) 3(S)!-2,3,4,5-Tetrahydro-3- 2-(acetylthio)-methyl!-1-oxo-3-phenylpropyl!amino!-2-oxo-1H-1-benzazepine-1-propanoicacid

(S)-2- (Acetylthio)methyl!benzenepropanoic acid obtained from theephedrine salt as described previously! was dissolved in dry methylenechloride, cooled down to 0° C., and treated with 1-hydroxybenzotriazolehydrate and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and a solutionof the product from Example 44(a) in dry methylene chloride according tothe procedure of Example 8 part (a) to afford the title product as asyrup. TLC (ethyl acetate:hexane, 1:1) R_(f) =0.58.

b) 3(S)!-2,3,4,5-Tetrahydro-3-2-(mercaptomethyl)-1-oxo-3-phenylpropyl!amino!-2-oxo-1H-1-benzazepine-1-propanoicacid

A solution of the product from part (a) in methanol was cooled down to0° C. and treated with 1N sodium hydroxide according to the procedure ofExample 8 part (b) to afford the title product as an amorphous solid;α!_(D) =+46.90° (c=0.608, methanol). TLC (chloroform:methanol:aceticacid, 20:1:1) R_(f) =0.42.

Anal.calc'd.for C₂₃ H₂₆ N₂ O₄ S.0.233 C₅ H₁₂.0.61 H₂ O: C, 63.89; H,6.65; N, 6.17; S, 7.06; Found: C, 63.89; H, 6.40; N, 6.18; S, 6.82.

EXAMPLE 46 1S- 1α, 9α(R*)!!-Octahydro-9-(2-mercapto-1-oxo-3-phenylpropyl)amino!-6,10-dioxo-6H-pyridazino 1,2-a!1,2!diazepine-1-carboxylic acid

a) (1S-cis)-Octahydro-9-phthalimido-6,10-dioxo-6H-pyridazinor 1,2-a!1,2!diazepine-1-carboxylic acid, 1,1-dimethylethyl ester

5,6-Dihydro-1,3(2H,4H)-pyridazinedicarboxylic acid,3-(1,1-dimethylethyl)-1-(phenylmethyl)ester prepared as described byAdams et al., Synthetic Communications, 18(18), 2225-2231 (1988)! wasreacted with (S)-2-phthalimidopentanedioic acid, 5-(phenylmethyl) esteraccording to the procedure described by Attwood et al.(J. Chem. Soc.Perkins Trans I, 1986, p. 1011-1019) affording (S)-2-2-phthalimido-1,5-dioxo-5-(phenylmethoxy)pentyl!-5,6-dihydro-1,3(2H,4H)-pyridazinedicarboxylicacid, 3-(1,1-dimethylethyl)-1-(phenylmethyl) ester.

A solution of this material (12.11 g., 18.5 mmol.) in drydimethylformamide (190 ml.) was treated with 10% palladium on carboncatalyst (372 mg.) and hydrogenated at room temperature for 24 hours.The mixture was filtered through a Celite pad, the clear dark filtrateobtained was evaporated to dryness and the syrup was obtainedredissolved in methanol (200 ml.). The solution was filtered throughanother Celite pad to remove remaining traces of the catalyst, and theclear filtrate was evaporated to dryness and dried in vacuo. The productobtained was dissolved in dry methylene chloride (185 ml.), cooled downto 0° C. (ice-salt bath) and treated with thionyl chloride (1.56 ml.,21.36 mmoles, 1.15 eq.). The reaction mixture was stirred at roomtemperature for 5.0 hours under argon, treated with a solution ofpotassium bicarbonate (3.95 g.) in water (34 ml.) and stirred for 10minutes. The phases were separated, re-extracting the aqueous phase withmore methylene chloride (270 ml.) and the combined organic extracts weredried (anhydrous sodium sulfate), filtered, evaporated to dryness anddried in vacuo.

The crude product mixture was chromatographed on a silica gel column(Merck), eluting the column with ethyl acetate:hexane mixtures (1:3;1:1) to give 3.053 g. of the title compound as a solid. TLC (ethylacetate:hexane, 1:1) R_(f) =0.40.

b) (1S-cis)-Octahydro-9-amino-6,10-dioxo-6H-pyridazino 1,2-a!1,2!diazepine-1-carboxylic acid, 1,1-dimethylethyl ester

A suspension of the product from part (a) (1.0 g., 2.41 mmol.) inabsolute ethanol was treated with hydrazine hydrate (0.26 ml., 2.2 eq.)and stirred at room temperature for one hour under argon. The mixturewas stripped to dryness, evaporated once from toluene (25 ml.) and theresidue obtained was stirred with 2.0M acetic acid (10 ml.) for 24 hoursunder argon. The solids were filtered off, washed with 2.0M acetic acid(5.0 ml.) and water (2×2.0 ml.), and the clear filtrate was adjusted topH 10.0 with solid sodium bicarbonate (1.8 g.). The mixture wasextracted with methylene chloride (2×25 ml) and the combined organicextracts were washed with brine (6.0 ml.), dried (anhydrous sodiumsulfate) and filtered. The clear solution was evaporated to dryness anddried in vacuo to give 755 mg. of title product as a syrup. TLC(methylene chloride:methanol, 9:1) R_(f) =0.20.

c) 1S- 1α, 9α(R*)!!-Octahydro-9-2-(acetylthio)-1-oxo-3-phenylpropyl!amino!-6,10-dioxo-6H-pyridazinor1,2-a! 1,2!diazepine-1-carboxylic acid, 1,1-dimethylethyl ester

(S)-2-(Acetylthio)benzenepropanoic acid, dicyclohexylamine salt (1.07g., 2.64 mmol.) was suspended in ethyl acetate (80 ml.), washed with 5%potassium bisulfate (5×12 ml.) and brine (14 ml.), dried (anhydrousmagnesium sulfate), filtered, evaporated to dryness and dried in vacuo.

The free acid was dissolved in dry methylene chloride (20 ml.), cooleddown to 0° C. (ice-salt bath), treated sequentially with a solution ofthe product from part (b) (755 mg., 2.41 mmol.) in dry methylenechloride (5.0 ml.), triethylamine (0.33 ml., 2.37 mmol.) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(1.08 g., 2.44 mmol.). The reaction mixture was stirred at 0° C. for 1.0hour and at room temperature for 2.0 hours under argon. The reactionmixture was stripped to dryness and the syrup obtained was redissolvedin ethyl acetate (80 ml.), washed with 0.5N hydrochloric acid (2×14ml.), water (14 ml.) and brine (14 ml.), dried (anhydrous magnesiumsulfate), filtered and evaporated to dryness. The crude product waschromatographed on a silica gel column (Merck), eluting the column withethyl acetate:hexane mixtures (1:3; 1:1), to give 747 mg. of titleproduct as a clear syrup. TLC (ethyl acetate:hexane, 1:1) R_(f) =0.23.

d) 1S- 1α,9α(R*)!!-Octahydro-9-2-(acetylthio)-1-oxo-3-phenylpropyl!amino!-6,10-dioxo-6H-pyridazino1,2-a! 1,2!diazepine-1-carboxylic acid

A solution of the product from part (c) (747 mg., 1.48 mmol.) in drymethylene chloride (10 ml.) was treated with anisole (0.69 ml., 6.35mmol.) followed by trifluoroacetic acid (1.04 ml., 13.5 mmol.) and thereaction mixture was stirred at room temperature under argon for 5.5days. The clear solution was stripped to dryness, evaporated from ethylacetate (2×100 ml.) and the crude product was chromatographed on asilica gel column (Merck), eluting the column with ethyl acetate:hexane(4:1) followed by ethyl acetate:hexane:acetic acid (85:10:5). Thedesired fractions were combined, stripped to dryness and evaporated fromtoluene (2×100 ml.). The syrup obtained was redissolved in ethyl acetate(59 ml.), washed with water (3×10 ml.) and brine (5.0 ml.), dried(anhydrous sodium sulfate), filtered, evaporated to dryness and dried invacuo to give 556 mg. of title product as a syrup. TLC (ethylacetate:acetic acid, 95:5) R_(f) =0.30.

e) 1S- 1α,9α(R*)!!-Octahydro-9-(2-mercapto-1-oxo-3-phenylpropyl)amino!-6,10-dioxo-6H-pyridazino 1,2-a!1,2!diazepine-1-carboxylic acid

A solution of the product from part (d) (556 mg., 1.24 mmol.) inmethanol (7.0 ml.) was cooled down to 0° C. (ice-salt bath), purged withargon for 30 minutes then treated with a previously purged (argon, 30minutes) solution of 1.0N sodium hydroxide (2.5 ml., 2.5 mmol.)maintaining the bubbling of argon throughout the addition and length ofthe reaction. The reaction mixture was stirred at 0° C. for 30 minutes,brought to pH 2.0 with 5% potassium bisulfate (11.0 ml) at 0° C., warmedup to room temperature and extracted with ethyl acetate (2×40 ml.). Thecombined organic extracts were washed with brine (11.0 ml.), dried(anhydrous sodium sulfate), filtered, evaporated to dryness and dried invacuo. The crude product was dissolved in methylene chloride (5.0 ml.)and treated portionwise with hexane (50 ml.) while scratching untilsolids were obtained. The solids were triturated with more hexane (50ml.) and pentane (2×50 ml.), stirring the solids with the first 50 ml.for 2.0 hours and with the next 50 ml. overnight at room temperatureunder argon. The product was dried in vacuo to give 468.5 mg. of titleproduct as a solid foam; α!_(D) =-83.5° (c=0.492, methanol). TLC (ethylacetate:acetic acid. 95:5) R_(f) =0.33.

Anal. calc'd. for C₁₉ H₂₃ N₃ O₅ S.0.34 H₂ O: C, 55.45; H, 5.80; N,10.21; S, 7.79; Found: C, 55.45; H, 5.95; N, 9.84; S, 7.49.

EXAMPLE 47 1S- 1α,9α(R*)!!-Octahydro-9-(2-mercapto-1-oxo-3-phenylpropyl)amino!-10-oxo-6H-pyridazino 1,2-a!1,2!diazepine-1-carboxylic acid

a) (1S-cis)-Octahydro-9-phthalimido-10-oxo-6H-pyridazino 1,2-a!1,2!diazepine-1-carboxylic acid, 1,1-dimethylethyl ester

A solution of the product from Example 46(a) (1.0 g., 2.35 mmole) in drytetrahydrofuran (8.0 ml.) was cooled down to about 5° C. (ice-waterbath), treated with 1.0M diborane/tetrahydrofuran (2.88 ml., 2.88 mmol.)over a period of 30 minutes, warmed up to room temperature and stirredovernight under argon. The reaction mixture was diluted with methylenechloride (14.0 ml.), treated with 2.0N hydrochloric acid (6.8 ml.) andstirred for 15 minutes. The mixture was then brought to pH 10.0 withanhydrous sodium bicarbonate (1.92 g.) and the phases separated,re-extracting the aqueous phase with more methylene chloride (30 ml.).The combined organic extracts were washed with brine (5.0 ml.), dried(anhydrous magnesium sulfate), filtered, evaporated to dryness and driedin vacuo. The crude product was chromatographed on a silica gel column(Merck), eluting the column with ethyl acetate:hexane mixtures (1:3;1:1) to give 877 mg. of title product as a syrup. TLC (ethylacetate:hexane, 1:1) R_(f) =0.63.

b) (1S-cis)-Octahydro-9-amino-10-oxo-6H-pyridazino 1,2-a!1,2!diazepine-1-carboxylic acid, 1.1-dimethylethyl ester

A solution of the product from part (a) (1.257 g., 3.0 mmol.) inabsolute ethanol (13.0 ml.) was treated with hydrazine hydrate (0.33ml., 2.2 eq.) according to the procedure of Example 46 part (b)affording 704 mg. of title product as a syrup. TLC (methylenechloride:methanol, 9:1) R_(f) =0.35.

c) 1S- (1α,9α(R*)!!-Octahydro-9-2-(acetylthio)-1-oxo-3-phenylpropyl!amino!-10-oxo-6H-pyridazino 1,2-a!1,2!diazepine-1-carboxylic acid, 1,1-dimethylethyl ester

(S)-2-(Acetylthio)benzenepropanoic acid, dicyclohexylamine salt (1.10g., 2.71 mmol.) was suspended in ethyl acetate (85 ml.), washed with 5%potassium bisulfate (5×12.4 ml.) and brine (14.4 ml.), dried (anhydrousmagnesium sulfate), filtered, evaporated to dryness and dried in vacuo.

The free acid was dissolved in dry methylene chloride (21 ml.). cooleddown to 0° C. (ice-salt bath), treated sequentially with a solution ofthe product from part (b) (704 mg., 2.48 mmol.) in dry methylenechloride (5.0 ml.), triethylamine (0.34 ml., 2.44 mmol.) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(1.113 g., 2.55 mmol.). The reaction mixture was stirred at 0° C. for1.0 hour and at room temperature for 2.5 hours under argon. The reactionmixture was stripped to dryness and the syrup obtained was re-dissolvedin ethyl acetate (80 ml.), washed with 0.5N hydrochloric acid (2×14.0ml.), water (14.0 ml.) and brine (14.0 ml.), dried (anhydrous magnesiumsulfate), filtered, evaporated to dryness and dried in vacuo. The crudeproduct was chromatographed on a silica gel column (Merck), eluting thecolumn with ethyl acetate:hexane (1:3) to give 1.085 g. of title productas a syrup. TLC (ethyl acetate:hexane, 1:1) R_(f) =0.53.

d) 1S- 1α,9α(R*)!!-Octahydro-9-(2-mercapto-1-oxo-3-phenylpropyl)amino!-10-oxo-6H-pyridazinor1,2-a!1,2!diazepine-1-carboxylic acid

A solution of the product from part (c) (1.085 g., 2.216 mmol.) in drymethylene chloride (15 ml.) was treated with anisole (1.03 ml., 9.5mmol.) followed by trifluoroacetic acid (1.56 ml., 20.2 mmol.) and thereaction mixture was stirred at room temperature under argon for 4.0days. The clear solution was stripped to dryness, evaporated from ethylacetate (2×150 ml) and the crude product suspended in a mixture of ethylacetate (10 ml.) and hexane (50 ml.). The solids were filtered off,washed well with hexane (50 ml.) then evaporated from toluene (2×100 ml)and dried in vacuo to give 865 mg. of 1S- 1α,9α(R*)!!-Octahydro-9-2-(acetylthio)-1-oxo-3-phenylpropyl!amino!-10-oxo-6H-pyridazino 1,2-a!1,2!diazepine-1-carboxylic acid as a solid.

The above material was suspended in methanol (15 ml.), cooled down to 0°C. (ice-salt bath), purged with argon for 30 minutes then treateddropwise with a previously purged solution of 1.0N sodium hydroxide(6.03 ml., 3 eq.), maintaining the bubbling of argon throughout theaddition and length of the reaction. The reaction mixture was stirred at0° C. for 30 minutes (the solids went into solution within the first 5minutes) brought to pH 2.0 with 5% potassium bisulfate (26.6 ml.),warmed up to room temperature and extracted with ethyl acetate (2×65ml.). The combined organic extracts were washed with brine (18 ml.),dried (anhydrous sodium sulfate), filtered, evaporated to dryness anddried in vacuo. The product was dissolved in methylene chloride (7.0ml.) and treated portionwise with hexane (70 ml.) while scratching untila solid was obtained. The solids were triturated with more hexane (100ml.) and pentane (2×100 ml.), stirring the solids with the first 100 ml.for 2.0 hours and the next 100 ml. overnight at room temperature underargon. The product was dried in vacuo to give 790.6 mg. of title productas a solid foam; α!_(D) =-44.4° (c=0.63, methanol). TLC (ethylacetate:acetic acid, 95:5) R_(f) =0.67.

Anal.calc'd. for C₁₉ H₂₅ N₃ O₄ S.0.2° C₅ H₁₂.0.80 H₂ O: C, 57.11; H,6.95; N, 9.99; S, 7.62; Found: C, 57.11; H, 6.72; N, 9.83; S, 7.44.

EXAMPLE 48 S-(R*,R*)!-Hexahydro-6-(2-mercapto-1-oxo-3-phenylpropyl)amino!-2-methyl-3,7-dioxo-1H-1,2-diazepine-1-aceticacid

a) 2- (1,1-Dimethylethoxy)carbonyl!hydrazino!acetic acid, ethyl ester

Triethylamine (13.94 ml., 0.1 mol.) was added to a solution of hydrazinecarboxylic acid, 1,1-dimethylethyl ester (13.216 g., 0.1 mole) inbenzene (100 ml.), followed by the addition of ethyl bromoacetate (11.09ml., 0.1 mol.). The reaction mixture was refluxed (oil bath, 95°-100°C.) for 14 hours, after which triethylamine (1.4 ml., 0.01 mol.) wasadded followed by ethyl bromoacetate (1.1 ml., 0.01 mole). Afterrefluxing for an additional 8 hours, triethylamine (2 ml., 0.015 mol.)and ethyl bromoacetate (1.4 ml., 0.013 mole) were added. The mixture wasallowed to reflux for another 14 hours (total 36 hours). After coolingto room temperature, the reaction mixture was filtered and the solidtriethylamine, hydrochloride salt was washed with ethyl acetate/hexane(1:1). The combined filtrate was diluted with ethyl acetate, washed withsaturated sodium bicarbonate, water, brine, dried (sodium sulfate) andfiltered. The filtrate was concentrated in vacuo to afford 19.38 g. ofcrude product as a yellow syrup which was used for the next reactionwithout purification.

b) 2- (1,1-Dimethylethoxy)carbonyl!-1-(phenylmethoxy)carbonyl!hydrazino! acetic acid, ethyl ester

Triethylamine (12.4 ml., 89 mmol.) was added to a solution of the crudeproduct from part (a) (19.38 g.) in benzene (120 ml.) followed by thedropwise addition of (phenylmethoxy)carbonyl!-chloride (13.4 ml., 89mmol.) in benzene (30 ml.) over 30 minutes. The resulting suspension wasstirred at room temperature under argon for 20 hours, then partitionedbetween ethyl acetate (500 ml.) and 1M potassium bisulfate solution. Theorganic phase was separated, washed with saturated sodium bicarbonate,water, brine, dried (sodium sulfate) and filtered. The filtrate wasconcentrated in vacuo and the residue was crystallized from ethylacetate/hexane to afford, after drying in vacuo over phosphoruspentoxide, 15.736 g. of the title product as a white crystallinecompound, m. p. 117°-119° C.

c) 2- (1,1-Dimethylethoxy)carbonyl!-1-(phenylmethoxy)carbonyl!-2-methyl!hydrazino!acetic acid, ethyl ester

Potassium carbonate (powdered and dried, 11.8 g., 85.15 mmol.) was addedto a solution of the product from part (b) (6.0 g., 17.03 mmol.) inanhydrous dimethylformamide (30 ml.) followed by the addition of methyliodide (5.3 ml, 85.15 mmol.). After stirring at 40° C. for 17 hours,additional methyl iodide (64 mmol.) was added and the reaction mixturestirred at 40° C. for an additional 28 hours. The suspension wasfiltered and to the filtrate was added 6.0 g. of fresh potassiumcarbonate (powdered and dried), followed by 5.0 ml. of methyl iodide.The suspension was stirred at 40° C. for 21 hours, then 1.2 ml. ofmethyl iodide was added and the reaction mixture stirred for additional17 hours until starting material disappeared on TLC. The reactionmixture was filtered and the collected solid was washed with ethylacetate. The filtrate was concentrated in vacuo to remove most ofdimethylformamide, then diluted with 500 ml. of ethyl acetate, washedwith water, 1M potasium bisulfate, water, brine and dried (magnesiumsulfate). The filtrate was concentrated and the residue dried in vacuoto give 6.285 g. of crude product as a colorless oil.

d) 2- (1,1-Dimethylethoxy)carbonyl!-2-methyl!hydrazino!acetic acid,ethyl ester

A suspension of the product from part (c) (6.285 g., 17.03 mmol.) andpalladium hydroxide (800 mg.) in ethanol (75 ml.) was vigorously stirredunder hydrogen (balloon) for 4 hours. The suspension was filtered usinga millipore filter unit. The filtrate was concentrated and the residuedried in vacuo to afford 4.3 g. of title product as a light yellow oil.

e) (S)-2-Phthalimido-1,5-pentanedioic acid, 5-(phenylmethyl)ester

N-(Carbethoxy)phthalimide (9.7 g., 44.24 mmol., 1.05 eq.) was added to asuspension of L-glutamic acid, 5-(phenylmethyl)ester (10.0 g., 42.14mmol.) and sodium bicarbonate (4.47 g., 42.14 mmole) in water (80 ml.)and dioxane (40 ml.). After stirring two hours, additionalN-(carbethoxy)phthalimide (4.4 g., 0.1 eq.) was added. The mixture wasstirred for additional 2 hours. The reaction mixture was adjusted to pH1-2 with solid potassium bisulfate, and extracted with ethyl acetate(3×150 ml.). The combined ethyl acetate extracts were washed with 1Mpotassium bisulfate, brine, dried (sodium sulfate) and filtered. Thefiltrate was concentrated in vacuo. The oily residue was taken intoethyl acetate and treated with dicyclohexylamine (8.40 ml., 42.14mmol.). Crystallization of the crude salt from ethyl acetate/hexanegave, after drying in vacuo, 13 g. of the title product as thedicyclohexylamine salt. The mother liquor was washed with 1M potassiumbisulfate (2×), water, brine, and dried (sodium sulfate). The filtratewas concentrated in vacuo. The oily residue was chromatographed using0.5% acetic acid in heptane/ethyl acetate (3:7) as a mobile phase. Thedesired fractions were collected and concentrated. The oily residue wasdried in vacuo to give 9.644 g. of the title product.

f) (S)-4-Phthalimido-5-oxo-5- 2-(1,1-dimethylethoxy)carbonyl!-1-(2-ethoxy-2-oxyethyl)-2-methylhydrazino!pentanoicacid, phenylmethyl ester

Phosphorus pentachloride (5.10 g., 24.5 mmol.) was added to a cold (0°C.) solution of the product from part (e) (about 17.10 mmol.) in ether(80 ml.). After stirring at 0° C. for 30 minutes and at room temperaturefor 30 minutes, the reaction mixture was concentrated in vacuo. Theresidue was stripped with toluene (3×) and dried in vacuo for 2 hours togive an oily compound that was used immediately in the followingreaction.

Sodium bicarbonate solution (4 g. in 46 ml. of water) was added to acold (0° C.) solution of the product from part (d) in toluene (40 ml.).With thorough stirring, the compound prepared above in toluene (30 ml.)was added dropwise via cannula. After addition, the reaction mixture wasstirred at room temperature under argon for 19 hours. The reactionmixture was diluted with ethyl acetate (300 ml.), washed with water, 5%potassium bisulfate, water, brine and dried (sodium sulfate). Thefiltrate was concentrated and the residue dried in vacuo to give thetitle compound as an oil.

g) (S)-4-Phthalimido-5-oxo-5-1-(2-ethoxy-2-oxyethyl)-2-methylhydrazino!pentanoic acid, phenylmethylester

Anisole (7.4 ml.) followed by trifluoroacetic acid (13.10 ml., 170mmol.) were added dropwise to a cooled (-10° C.) solution of the crudeproduct from part (f) in methylene chloride (55 ml.). After the additionwas completed, the reaction mixture was stirred at -10° C. for one hour.The reaction mixture was then allowed to warm to room temperature andstirring continued for 14 hours. After removal of the volatiles invacuo, the residue was taken into 200 ml. of ethyl acetate, washed withsaturated sodium bicarbonate with caution, then water, brine, and dried(sodium sulfate). The filtrate was concentrated in vacuo and the residuechromatographed using 20-40% ethyl acetate/hexane as a mobile phase. Thedesired fractions were collected and concentrated and the residue driedin vacuo to yield 7.254 g. of title product as a pale yellow oil.

h) (S)-4-Phthalimido-5-oxo-5-1-(2-ethoxy-3-oxyethyl)-2-methylhydrazino!pentanoic acid

Palladium hydroxide (1.0 g.) was added to a solution of the product frompart (g) (6.436 g., 13.38 mmol.) in warm ethanol (100 ml.). Thesuspension was vigorously stirred under hydrogen (balloon) for 4 hours.The suspension was filtered and the catalyst washed with ethanol. Thecombined filtrate was concentrated. The residue was stripped withtoluene (2×) and dried in vacuo overnight to yield 5.86 g. of product asa colorless oil which was used for the next reaction withoutpurification.

i)(S)-Hexahydro-2-methyl-3,7-dioxo-6-phthalimido-1H-1,2-diazepine-1-aceticacid, ethyl ester

Thionyl chloride (1.1 ml.) was added dropwise to a cooled (0° C.)solution of the product from part (h) (5.86 g., 13.38 mmol.) inmethylene chloride (120 ml.). The reaction mixture was stirred at 0° C.for 15 minutes and then at room temperature for 3 hours. Additionalthionyl chloride (0.3 ml., for a total of 1.4 ml.) was added and thereaction mixture was stirred for another 3 hours, then quenched withpotassium bicarbonate solution (2.7 g. of potassium bicarbonate in 27ml. of water). The separated organic phase was washed with saturatedsodium bicarbonate. The aqueous phase was extracted with methylenechloride (2×). The combined methylene chloride phase was washed withwater, brine and dried (magnesium sulfate). The filtrate wasconcentrated and the residue dried in vacuo to give 4.70 g. of desiredproduct.

i) (S)-Hexahydro-2-methyl-3,7-dioxo-6-amino-1H-1,2-diazepine-1-aceticacid, ethyl ester

Hydrazine monohydrate (255 μl., 5.25 mmol.) was added to a suspension ofthe product from part (i) (1.867 g., 5.0 mmol.) in ethanol (30 ml.) andmethylene chloride (10 ml.). After stirring for 2 hours, the volatileswere removed in vacuo and the residue stripped with toluene (2×), thendried in vacuo. The residue was taken into 2M aqueous acetic acid (20ml.) and the resulting solution was stirred at room temperature for 14hours. The suspension was filtered. The collected filtrate was basifiedwith solid sodium bicarbonate to pH 10 and extracted with methylenechloride (3×). The combined methylene chloride phase was washed with 50%brine, brine, dried (sodium sulfate), filtered and evaporated. Theresidue was chromatographed using 2.5% methanol/methylene chloride as amobile phase to afford 568 mg. of title product as a pale yellow oil.

k) S-(R*,R*)-Hexahydro-6-2-(acetylthio)-1-oxo-3-phenylpropyl!amino!-2-methyl-3,7-dioxo-1H-1,2-diazepine-1-aceticacid, ethyl ester

Triethylamine (302 μl, 2.171 mmol.) was added to a cooled (0° C.)solution of (S)-2-(acetylthio)benzenepropanoic acid (obtained from thedicyclohexylamine salt as described previously, 486 mg., 2.17 mmol)followed by the product from part (j) (480 mg., 1.973 mmol.) inmethylene chloride (3 ml.), andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(960 mg., 2.171 mmol.) The mixture was stirred at 0° C. for 1 hour, thenat room temperature for 2 hours. The volatiles were removed in vacuo.The residue was taken into ethyl acetate (100 ml.), washed with 5%potassium bisulfate, 50% saturated sodium bicarbonate, brine, dried(magnesium sulfate), filtered and evaporated to dryness. The crudeproduct was flash chromatographed using 50-70% ethyl acetate/hexane as amobile phase to give 824 mg. of title product as a white foamingcompound.

l) S-(R*,R*)!-Hexahydro-6-(2-mercapto-1-oxo-3-phenylpropyl)amino!-2-methyl-3,7-dioxo-1H-1,2-diazepine-1-aceticacid

A solution of the product from part (k) (800 mg.,1.78 mmol) in methanol(9 ml.) cooled at 0° C. was purged with argon for 30 minutes, thentreated dropwise with a previously purged 1M sodium hydroxide solution(7.12 m., 4.0 equiv.). The reaction was stirred at 0° C., whilemaintaining the bubbling of argon, for 1.5 hour, then acidified with 1Mpotassium bisulfate to pH 1-2 and extracted with ethyl acetate (3×). Thecombined ethyl acetate extract was washed with brine (2×), dried(magnesium sulfate), filtered and evaporated to dryness. The residue wasflash chromatographed using 2% acetic acid/ethyl acetate as a mobilephase to give 668 mg. of desired product as a white foaming compound.Chloroform was used in the pooling of product-containing columnfractions. α!_(D) =-54.8° (c=0.8, methanol). TLC (3% acetic acid/ethylacetate) R_(f) =0.12.

Anal. calc'd. for C₁₇ H₂₁ N₃ O₅ S.0.57 CHCl₃ : C, 47.16; H, 4.86; N,9.39; S, 7.16; Found: C, 47.48; H, 4.56; N, 9.01; S, 7.17.

EXAMPLE 49 S-(R*,R*)!-Hexahydro-6-(2-mercapto-1-oxo-3-phenylpropyl)amino!-2-methyl-7-oxo-1H-1,2-diazepine-1-aceticacid

a) (S)-Hexahydro-2-methyl-7-oxo-6-phthalimido-1H-1,2-diazepine-1-aceticacid, ethyl ester

A solution of the product from Example 48 (i) (375 mg., 1.0 mmole) indry tetrahydrofuran (2.4 ml.) was cooled to 0° C. and treated dropwisewith a 1M solution of diborane in tetrahydrofuran. After the additionwas completed, the reaction solution was stirred at 0° C. for 30 minutes(at that time it became a gel). The cooling bath was removed, and thesemi-solid mixture was stirred at room temperature for an additional onehour before it was diluted with 2 ml. of methylene chloride and 2 ml. of2M aqueous hydrochloric acid. After stirring for 15 minutes, the mixturewas diluted with 20 ml. of methylene chloride, and washed with saturatedsodium bicarbonate with caution. The separated aqueous phase wasextracted with methylene chloride (3×). The combined methylene chlorideextract was washed with 50% brine, brine, and dried (sodium sulfate).The filtrate was evaporated in vacuo to dryness to afford 344 mg. ofcrude product as an oil, which was used for the next reaction withoutpurification.

b) (S)-Hexahydro-2-methyl-7-oxo-6-amino-1H-1,2-diazepine-1-acetic acid,ethyl ester

A solution of the product from part (a) (344 mg., 0.958 mmol.) inethanol (3 ml.) was treated with hydrazine monohydrate (54.8 μl., 1.13mmol.) according to the procedure of Example 48 part (j) affording 169mg. of title product as a pale yellow oil.

c) S-(R*,R*)!-Hexahydro-6-2-(acetylthio)-1-oxo-3-phenylpropyl!amino!-2-methyl-7-oxo-1H-1,2-diazepine-1-aceticacid, ethyl ester

A cold (0° C.) solution of (S)-2-(acetylthio)benzenepropanoic acid(obtained from the dicyclohexylamine salt as previously described, 198mg., 0.885 mmol.) in methylene chloride (1 ml.) was treated withtriethylamine (123 μl., 0.88 mmol.), the product from part (b) (169 mg.,0.738 mmol.) in methylene chloride (2 ml.) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(392 mg., 0.885 mmol.) The mixture was stirred at 0° C. for 1 hour, thenat room temperature for 2 hours. The volatiles were removed in vacuo.The residue was taken into ethyl acetate (50 ml.), washed with 5%potassium bisulfate, saturated sodium bicarbonate, 50% brine, brine, anddried (magnesium sulfate). The filtrate was evaporated to dryness andthe residue flash chromatographed using 40-50% ethyl acetate/hexane as amobile phase to give 260.5 mg. of title product as a colorless oil.

d) S-(R*,R*)!-Hexahydro-6-(2-mercapto-1-oxo-3-phenylpropyl)amino!-2-methyl-7-oxo-1H-1,2-diazepine-1-aceticacid

A solution of the product from part (c) (235 mg., 0.54 mmol.) inmethanol (3 ml.) cooled at 0° C. was purged with argon for 30 minutes,then treated dropwise with a previously purged 1M sodium hydroxidesolution (2.20 ml., 4.0 equiv.). The reaction was stirred at 0° C.,while maintaining the bubbling of argon for 2 hours, then acidified with1M potassium bisulfate to pH 1-2 and extracted with ethyl acetate (3×).The combined ethyl acetate extracts were washed with brine (2×), dried(sodium sulfate), filtered and evaporated to dryness. The residue wasflash chromatographed using 2% acetic acid/ethyl acetate as a mobilephase to give 182.2 mg. of desired product as a white foaming compound;α!_(D) =-9.6° (c=0.3, methanol). TLC (3% acetic acid in ethyl acetate)R_(f) =0.26.

Anal. calc'd. for C₁₇ H₂₃ N₃ O₄ S.0.2 H₂ O: C, 55.32; H, 6.39; N. 11.39;S, 8.69; Found: C, 55.73; H, 6.44; N, 10.98; S, 8.56.

EXAMPLE 50 S-(R*,R*)!-2,3,4,5-Tetrahydro-3-(2-mercapto-1-oxohexyl)amino!-2-oxo-1H-benzazepine-1-acetic acid

a) (S)-2-Bromohexanoic acid

Potassium bromide (15.9 g., 133 mmol.) was added to a stirred solutionof D-norleucine (5.0 g., 38 mmol.) in 2.5N sulfuric acid (77 ml.) atroom temperature. The reaction mixture was cooled to -10° C. and solidsodium nitrite (3.94 g., 57 mmol.) was added portionwise, maintainingthe temperature between -10° and -5° C. After addition was complete, thefoamy reaction was stirred for 1 hour and then warmed to roomtemperature and stirred for another hour. The reaction mixture was thenextracted twice with ether, the ether extracts were washed once withwater, dried (magnesium sulfate), filtered and evaporated to give 3.3 g.of crude title product.

b) (S)-2-(Acetylthio)hexanoic acid, dicyclohexylamine salt

To a stirred slurry of potassium thioacetate (2.11 g., 18.5 mmol.) in 50ml. of dry acetonitrile at room temperature under argon was added asolution of the product from part (a) (3.27 g., 16.8 mmol.) in 26 ml. ofacetonitrile. The reaction was stirred 5 hours. The resulting slurry wasfiltered and evaporated. The residue was redissolved in ethyl ether,washed once with 5% potassium hydrogen sulfate solution and once withbrine, dried (magnesium sulfate) and evaporated. The residue wasdissolved in ether (64 ml.) and treated with dicyclohexylamine (3.4 ml.,16.8 mmol.). The ethereal solution was concentrated in vacuo, andtriturated from hexanes to give a white solid which was recrystallizedfrom ethyl ether/hexanes to give the title product. The mother liquorwas concentrated and recrystallized twice to provide a total yield of2.2 g. of title product; m.p. 145°-147° C.; α!_(D) =-33.8° (c=1.08,chloroform).

c) S-(R*,R*)!-2,3,4,5-Tetrahydro-3-(2-mercapto-1-oxohexyl)amino!-2-oxo-1H-benzazepine-1-acetic acid, ethylester

A stirred suspension of the product from part (b) (295 mg., 0.795 mmol.)in 5 ml. of ethyl acetate was washed twice with 5 ml. portions of 5%potassium hydrogen sulfate solution. The organic extract was dried(sodium sulfate), filtered, concentrated and dried in vacuo for 20minutes. The resulting oil was dissolved in 3 ml. of methylene chlorideand stirred under argon at 0° C. To this solution was added a solutionof (S)-2,3,4,5-tetrahydro-3-amino-2-oxo-1H-benzazepine-1-acetic acid,ethyl ester prepared as described by watthey et al., J. Med. Chem., 28,p. 1511-1516 (1985)! (149 mg., 0.57 mmol.) in methylene chloride (3 ml.)then triethylamine (83 μl., 0.60 mmol.) and finallybenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(264 mg., 0.60 mmol.). After 1 hour, the reaction was warmed to roomtemperature and stirred 90 minutes. The resulting solution wasevaporated at less than 30° C. and the residue redissolved in ethylacetate. The solution was washed once with 1M hydrochloric acid, oncewith water, once with a saturated solution of sodium bicarbonate andonce with brine. The organic layer was dried (magnesium sulfate),filtered and evaporated. Purification by flash chromatography (elutingwith 1:3 ethyl acetate/hexanes) provided 193 mg. of the title product;α!_(D) =-284.3° (c=0.21, chloroform).

d) S-(R*,R*)!-2,3,4,5-Tetrahydro-3-(2-mercapto-1-oxohexyl)amino!-2-oxo-1H-benzazepine-1-acetic acid

A solution of the product from part (c) (183 mg., 0.42 mmol.) in 3.8 ml.of methanol was purged with nitrogen for 5 minutes and cooled to 0° C.To this solution was added dropwise 3.8 ml. of nitrogen-purged 1M sodiumhydroxide. Nitrogen was slowly bubbled through the solution during thereaction. After one hour, the reaction was warmed to room temperatureand stirred one hour. The reaction was acidified with a 5% potassiumbisulfate solution and extracted with ethyl acetate, the extracts werewashed with water and a saturated solution of sodium chloride, dried(magnesium sulfate) and evaporated. Reevaporation from hexanes yielded awhite solid. The solid was gently heated in ethyl ether and crystallizedwith hexanes to give 117 mg. of title product as a white solid; m. p.151°-153° C.; α!_(D) =-214.1° (c=0.46, chloroform). TLC (ethylacetate/hexane/acetic acid, 4:4:0.1) R_(f) =0.23.

Anal. calc'd.for C₁₈ H₂₄ N₂ O₄ S: C, 59.32; H, 6.64; N, 7.69; S, 8.80;Found: C, 59.10; H, 6.62; N, 7.72; S, 8.63.

EXAMPLE 51 3S- 3α(R*),7β!!-Hexahydro-7-(2-hydroxyethyl)-3-(2-mercapto-1-oxo-3-phenylpropyl)amino!-2-oxo-1H-azepine-1-acetic acid

a) (3S-trans)-Hexahydro-3-(1,1-dimethylethoxy)-carbonyl!amino!-2-oxo-7-(2-propenyl)-1H-azepine-1-aceticacid, methyl ester

Hydrazine monohydrate (133 μl., 2.70 mmol.) was added dropwise to asolution of(3S-trans)-hexahydro-3-phthalimido-2-oxo-7-(2-propenyl)-1H-acetic acid,methyl ester prepared as set forth in Example 36 part (e), 609 mg., 2.45mmol.!. The reaction was stirred at room temperature for 64 hours, thenfiltered to remove the solid byproducts. The filtrate was concentratedin vacuo, dissolved in methylene chloride, refiltered and reconcentratedto give a crude oil. The crude oil was dried under vacuum to give 656mg. of crude(3S-trans)-hexahydro-3-amino-2-oxo-7-(2-propenyl)-1H-azepine-1-aceticacid, methyl ester as a yellow oil.

To a solution of this crude amine (589 mg., 2.45 mmol.) in methylenechloride (10 ml.), purged with argon, was added 510 μl. (3.68 mmol.) oftriethylamine. The reaction mixture was stirred 10 minutes, then 642 mg.(2.94 mmol.) of di-t-butyl dicarbonate was added. The reaction wasstirred at room temperature for 16 hours, followed by the addition of asecond portion of 170 μl (1.23 mmol.) of triethylamine and 160 mg. (0.74mmol.) of di-t-butyl dicarbonate. The reaction was sitrred an additional16 hours at room temperature, then diluted with 20 ml. of methylenechloride. The organic layer was washed with 2-10 ml. portions of water,dried (magnesium sulfate) and concentrated in vacuo to give a crude oil.The oil was flash chromatographed (Merck silica, 25×120 mm., 1:6 ethylacetate/hexane, then 1:4 ethyl acetate/hexane) to give 651 mg. of titleproduct as a clear oil.

b) (3S-trans)-Hexahydro-3-(1,1-dimethylethoxy)-carbonyl!amino!-2-oxo-7-(hydroxyethyl)-1H-azepine-1-aceticacid, methyl ester

To a solution of the product from part (a) (554 mg., 1.63 mmol.) in 3ml. water/3 ml. dioxane was added 731 mg. (3.42 mmol.) of sodiumperiodate, followed after 10 minutes by the dropwise addition of 400 μl.(0.98 mmol.) of osmium tetroxide. The reaction was stirred at roomtemperature for 16 hours, filtered and rinsed with ethyl acetate. Theresulting filtrate was concentrated in vacuo without heat and flashchromatographed (Merck silica, 25×120 mm., 1:4 ethyl acetate/hexane-nopressure) to give 309 mg. of (3S-trans)-hexahydro-3-(1,1-dimethylethoxy)carbonyl!amino!-2-oxo-7-acetaldehyde-1H-azepine-1-aceticacid, methyl ester as a clear oil.

To a solution of this aldehyde (309 mg., 0.90 mmol.) in methanol (5ml.), cooled to 0° C., was added portionwise 68 mg. (1.80 mmol.) ofsodium borohydride. The reaction was stirred at 0° C. for 1.5 hours,then quenched by the dropwise addition of 0.5 ml. water and warmed toroom temperature. The mixture was partitioned between 25 ml. ethylacetate/25 ml. 1M hydrochloric acid; the aqueous layer was extractedwith 2-20 ml. portions of ethyl acetate. The combined ethyl acetatelayers were washed with 10 ml. of saturated sodium bicarbonate and 10ml. brine, dried (magnesium sulfate) and concentrated in vacuo to give acrude oil. The oil was flash chromatographed (Merck silica, 25×90 mm.,2:1 ethyl acetate/hexane, then ethyl acetate) to give 292 mg. of titleproduct as a clear oil.

c) 3S- 3α(R*),7β!!-Hexahydro-3-2-(acetylthio)-1-oxo-3-phenylpropyl!amino!-7-(2-hydroxyethyl)-2-oxo-1H-azepine-1-aceticacid, methyl ester

To a solution of the product from part (b) (292 mg., 0.85 mmol.) indioxane (1 ml.), cooled to 0° C., was added portionwise 2.5 ml. (9.34mmol., 4M) of hydrochloric acid/dioxane. The reaction was warmed to roomtemperature and stirred for 16 hours, then concentrated in vacuo andazeotroped with toluene to give 248 mg. of(3S-trans)-hexahydro-3-amino-2-oxo-7-(2-hydroxyethyl)-1H-azepine-1-aceticacid, methyl ester, hydrochloride salt as a crude oil.

To a solution of this amine, hydrochloride salt (189 mg., 0.67 mmol.)and (S)-2-(acetylthio)-benzenepropanoic acid (prepared from thedicyclohexylamine salt as described previously, 157 mg., (0.74 mmol.) inmethylene chloride (10 ml.), cooled to 0° C., was added triethylamine(230 μl., 1.68 mmol.). The mixture was stirred for 20 minutes, thenbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(327 mg., 0.74 mmol.) was added. The reaction was stirred at 0° C. forone hour, then at room temperature for 3 hours. The reaction mixture waspartitioned between 20 ml. ethyl acetate/20 ml. 5% potassium bisulfatesolution. The water layer was separated and extracted with 2-20 ml.portions of ethyl acetate; the combined ethyl acetate layers were washedwith 20 ml. of 5% potassium bisulfate solution, 20 ml. of saturatedsodium bicarbonate, 2-20 ml. portions of brine, dried (magnesiumsulfate) and concentrated in vacuo to give a crude oil. The oil wasflash chromatographed (Merck silica, 25×80 mm., 1:4 ethylacetate/hexane) to give 84 mg. of title product as a white foam.

d) 3S- 3α(R*),7β!!-Hexahydro-7-(2-hydroxyethyl)-3-(2-mercapto-1-oxo-3-phenylpropyl)amino!-2-oxo-1H-azepine-1-acetic acid

A solution of the product from part (c) (84 mg., 0.19 mmol.) in methanol(2 ml.) was purged with argon for 30 minutes and cooled to 0° C. To thissolution was added dropwise 2 ml. of 1M sodium hydroxide, also purgedwith argon for 30 minutes and cooled to 0° C. The reaction was stirredat 0° C. for 1 hour, with continuous argon purging, then acidified to pH2 with 5% potassium bisulfate solution. The mixture was extracted with3-20 ml. portions of ethyl acetate; the combined ethyl acetate layerswere dried (magnesium sulfate) and concentrated in vacuo to give a crudefoam. The foam was flash chromatographed (Merck silica, 15×60 mm.,0.5:5:95 acetic acid/methanol/methylene chloride) to give a white foam,which was azeotroped with toluene and dried in vacuo to give 48 mg. oftitle product as a white foam; α!_(D) =-42.9° (c=1.0, CDCl₃) TLC (aceticacid:methanol:methylene chloride, 1:10:90) R_(f) =0.25.

Anal. Calc'd. for C₁₉ H₂₆ N₂ SO₅.0.5 H₂ O: C, 56.55; H, 6.75; N, 6.94;S, 7.94; Found: C, 56.55; H, 6.64; N, 6.77; S, 7.51.

EXAMPLE 52 1S- 1α,9α(R*)!!-Octahydro-9-2-mercapto-1-oxo-3-(2-thienyl)propyl!amino!-10-oxo-6H-pyridazino 1,2-a!1,2!diazepine-1-carboxylic acid

a) (S)-α-(Acetylthio)-2-thiophenepropanoic acid

Potassium chloride (3.0 g., 40.1 mmol.) was added to a solution ofβ-(2-thienyl)-D-alanine (1.37 g., 8.03 mmol.) in 2.5N hydrochloric acid(25 ml.) at room temperature under argon. After stirring for 10 minutes,the resulting mixture was cooled to 0° C. and treated with sodiumnitrite (720 mg., 10.44 mmol.). After 2.5 hours, the reation mixture waswarmed to room temperature and was stirred 1 hour. The mixture waspartitioned between water and ethyl acetate and the organic layer wasdried (sodium sulfate), filtered, and concentrated. The residue wasflash chromatographed (Merck silica gel) eluting with 1% acetic acid in3:1 hexane/ethyl acetate to give 760 mg. of(R)-α-chloro-2-thiophenecarboxylic acid as a yellow oil.

Cesium thioacetate (2.95 g., 14.19 mmol.) was added to a solutioncontaining the above chloride (750 mg., 4.73 mmol.) in dimethylformamide(15 ml.) at room temperature under argon. After stirring for 2 hours,the reaction mixture was partitioned between 10% potassium bisulfate andethyl acetate. The organic layer was washed with brine, dried (sodiumsulfate), filtered, and concentrated and the residue was flashchromatographed (Merck silica gel) eluting with 1% acetic acid in 4:1hexane/ethyl acetate to give 500 mg. of the title product as an oil. TLC(2% acetic acid in 3:1 ethyl acetate/hexane) Rf 0.73.

b) 1S-{1α,9α(R*)!}-Octahydro-9-2-(acetylthio)-1-oxo-3-(2-thienyl)propyl!amino!-10-oxo-6H-pyridazino1,2-a! 1,2!diazepine-1-carboxylic acid

The product from part (a) (246 mg., 1.07 mmol.) and(1S-cis)-Octahydro-9-amino-10-oxo-6H-pyridazino 1,2-a!1,2!diazepine-1-carboxylic acid, 1,1-dimethyethyl ester from Example47(b) (370 mg., 1.17 mmol.) were dissolved in methylene chloride (10ml.) at room temperature under argon. The resulting mixture was cooledto 0° C. and triethylamine (0.15 ml., 1.07 mmol.) was added. Theresulting mixture was stirred for 5 minutes thenbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(517 mg., 1.17 mmol. was added. After being stirred at 0° C. for 1 hour,the reaction mixture was warmed to room temperature and was stirred for16 hours. The volatiles were evaporated and the residue was dissolved inethyl acetate and washed successively with 1N hydrochloric acid, water,50% saturated sodium bicarbonate, and brine. The organic layer was dried(sodium sulfate), filtered, and concentrated and the residue was flashchromatographed (Merck silica gel ) eluting with 3:2 hexane/ethylacetate. The product was resubjected to flash chromatography elutingwith 3:1 hexane/ethyl acetate to give 395 mg. of 1S-1α,9α(R*)!!octahydro-9-2-(acetylthio)-1-oxo-3-(2-thienyl)propyl!amino!-10-oxo-6H-pyridazino1,2-a! 1,2!diazepine-1-carboxylic acid, 1,1-dimethylethyl ester as awhite foam. TLC (ethyl acetate:hexane, 1:1) Rf=0.43.

Anisole (0.38 ml., 3.52 mmol.) was added to a solution of the aboveproduct(390 mg., 0.82 mmole) in methylene chloride (6 ml.) at roomtemperature under argon. The resulting mixture was treated withtrifluoroacetic acid (0.58 ml., 7.5 mmol.) and was stirred for 36 hours.The volatiles were removed and the residue was chased with toluene andevacuated to give 380 mg. of a yellow oil. The oil was purified bycolumn chromatography (Merck silica gel) eluting with 1% acetic acid in1:1 ethyl acetate/hexane followed by 1% acetic acid in 2:1 ethylacetate/hexane to give 360 mg. of the title product. TLC (1% acetic acidin 1:1 ethyl acetate/hexane) Rf=0.28.

c) 1S- 1α,9α(R*)!!-Octahydro-9-2-mercapto-1-oxo-3-(2-thienyl)propyl!amino!-10-oxo-6H-pyridazino 1,2-a!1,2!diazepine-1-carboxylic acid

A solution of the product from part (b) (328 mg., 0.75 mmol.) inmethanol (5 ml., deoxygenated via argon bubbling) was cooled to 0° C.and treated with 1N sodium hydroxide (4 ml., deoxygenated via argonbubbling). The resulting mixture was stirred under argon for 1 hour. Themixture was acidified with 10% potassium bisulfate and extracted withethyl acetate. The organic layer was washed successively with water andbrine, dried (sodium sulfate), filtered and concentrated to give a clearoil. This residue was flash chromatographed (Merck silica gel) elutingwith 1% acetic acid in 1:2 hexane/ethyl acetate. The fractionscontaining clean desired product were combined, stripped, azeotropedwith ethyl acetate, and washed with water to remove any acetic acid. Theorganic layer was dried (sodium sulfate), filtered and concentrated. Theresidue was taken up in ethyl acetate and triturated with hexane. Thesolvent was removed and the residue was slurried in hexane, stripped,and dried in vacuo to give 165 mg. of title product as a white powderyfoam. α!_(D) =131.6° (c=0.43, methylene chloride) TLC (1% acetic acid in2:1 ethyl acetate/hexane) R_(f) =0.36.

Anal. calc'd for C₁₇ H₂₃ N₃ O₄ S₂. 0.21 H₂ O.0.09 C₆ H₁₄.0.13 C₄ H₈ O₂ :C, 51.58; H, 6.17; N, 9.99; S, 15.25. Found: C, 51.24; H, 6.08; N, 9.69;S, 15.22.

EXAMPLE 53 1S- 1α,8α(R*)!!-Hexahydro-8-(2-mercapto-1-oxo-3-phenylpropyl)amino!-9-oxo-1H,5H-pyrazolor 1,2-a!1,2!diazepine-1-carboxylic acid

a) 1- (Phenylmethoxy)carbonyl!-3-pyrazolidinecarboxylicacid,1,1-dimethylethyl ester

A solution of 3-pyrazolidinecarboxylic acid, 1,1-dimethylethyl ester(10.935 g., 63.5 mmol.) in dry acetonitrile (90 ml.) was cooled to 0° C.(ice-salt bath) and treated with dry pyridine (11.0 ml.) followed by asolution of benzylchloroformate (12.54 g., 10.5 ml., 69.9 mmol.) in dryacetonitrile (25 ml.). The reaction was stirred at 0° C. for 3 hours,evaporated to dryness and the syrup obtained was redissolved in ethylacetate (250 ml.). The solution was washed with 5% sodium bicarbonate(2×25 ml.) and brine (25 ml.), dried (anhydrous sodium sulfate),filtered, evaporated to dryness and dried in vacuo. The crude productmixture was chromatographed on a silica gel column (Merck), eluting thecolumn with ethyl acetate:hexane mixtures (1:4; 1:2) to give 11.144 g.of title product as a syrup. TLC(ethyl acetate:hexane, 1:1) R_(f) =0.25.

b) (S)-2-2-Phthalimido-1,5-dioxo-5-(phenylmethoxy)pentyl!-1,3-pyrazolidinedicarboxylicacid, 3-(1,1-dimethylethyl)-1-phenylmethyl ester

The dicylcohexylamine salt of (S)-2-phthalimidopentanedioic acid,5-(phenylmethyl)ester (11.548 g., 21 mmol.) was suspended in ethylacetate (700 ml.), washed with 5% potassium bisulfate (5×100 ml.) andbrine (100 ml.), dried (anhydrous sodium sulfate), filtered, evaporatedto dryness and dried in vacuo.

The free acid obtained was dissolved in dry ether (100 ml.), cooled to0° C. (ice-salt bath), treated with phosphorous pentachloride (4.45 g.,21 mmol.) and stirred at 0° C. for 30 minutes then at room temperaturefor 15 minutes. The reaction mixture was evaporated to dryness,evaporated from toluene (2×230 ml.) and dried in vacuo. The crude acidchloride was dissolved in toluene (46 ml.), added to a cooled solution(10° C., ice-water bath) of the product from part (a) (5.52 g., 18mmol.) in toluene (35 ml.)-sodium bicarbonate (4.77 g. in 46 ml. water),warmed up to room temperature and stirred under argon for 20 hours. Thereaction mixture was diluted with ethyl acetate (650 ml.), washed with5% potassium bisulfate (2×140 ml.) and brine (140 ml.), dried (anhydroussodium sulfate), filtered, evaporated to dryness and dried in vacuo togive 11.587 g. of title product.

c) (1S-cis)-Hexahydro-8-phthalimido-5,9-dioxo-1H,5H-pyrazolo 1,2-a!1,2!diazepine-1-carboxylic acid, 1,1-dimethylethyl ester

A solution of the product from part (b) (12.653 g., 18 mmol.) in drydimethylformamide (196 ml.) was treated with 10% palladium on carboncatalyst (2.19 g.) and hydrogenated (balloon) at room temperature for 24hours. The reaction mixture was diluted with methanol (200 ml.) andfiltered through a Celite pad, washing the pad well with methanol (2×200ml.). The clear filtrate was evaporated to dryness and dried in vacuo togive a light goldcolored syrup. The crude product was dissolved in drymethylene chloride (185 ml.), cooled to 0° C. (ice-salt bath), treatedwith thionyl chloride (1.62 ml., 22.2 mmol.), stirred at 0° C. for 15minutes then at room temperature for 6.0 hours. The reaction mixture wasquenched with a solution of potassium bicarbonate (3.93 g.) in water (34ml.), stirred for 10-15 minutes then extracted with methylene chloride(2×290 ml.). The combined organic extracts were dried (anhydrous sodiumsulfate), filtered, evaporated to dryness and dried in vacuo The crudeproduct mixture was chromatographed on a silica gel column (Merck),eluting the column with ethyl acetate:hexane mixtures (1:3; 1:2) to give2.427 g. of title TLC(ethyl acetate:hexane, 1:1) R_(f) =0.37.

d) (1S-cis)-Hexahydro-8-phthalimido-9-oxo-1H,5H-pyrazolo 1,2-a!1,2!diazepine-1-carboxylic acid, 1,1-dimethylethyl ester

A solution of the product from part (c) (607 mg., 1.43 mmol.) in drytetrahydrofuran (12 ml.) was cooled to 0° C. (ice-salt bath) and treatedwith 1.0M diborane/tetrahydrofuran according to the procedure of Example47 part (a) to give 538 g. of title product as a syrup. TLC (ethylacetate:hexane, 1:1) R_(f) =0.38.

e) (1S-cis)-Hexahydro-8-amino-9-oxo-1H,5H-pyrazolo 1,2-a!1,2!diazepine-1-carboxylic acid, 1,1-dimethylethyl ester

A solution of the product from part (d) (505 mg., 1.25 mmol.) inabsolute ethanol (5.5 ml.) was treated with hydrazine hydrate (0.14 ml.,2.2 eq.) according to the procedure of Example 46 part (b) affording 312mg. of title compound as a syrup. TLC (methylene chloride:methanol, 9:1)R_(f) =0.63.

f) 1S- 1α,8α(R*)!!-Hexahydro-8-2-(acetylthio)-1-oxo-3-phenylpropyl!amino!-9-oxo-1H,5H-pyrazolo 2-a!1,2!diazepine-1-carboxylic acid

(S)-2-(Acetylthio)benzenepropanoic acid (obtained from 554 mg. of thedicyclohexylamine salt as previously described) was dissolved inmethylene chloride (11 ml.), cooled to 0° C. (ice-salt bath), andtreated sequentially with a solution of the product from part (e) (350mg., 1.25 mmol.) in dry methylene chloride (2.5 ml.), triethylamine(0.17 ml., 1.22 mmol.), and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (561 mg., 1.29 mmol.)according to the procedure of Example 47 part (c) to give 400 mg. of 1S-1α,8α(R*)!!-hexahydro-8-2-(acetylthio)-1-oxo-3-phenylpropyl!amino!-9-oxo-1H,5H-pyrazolo 1,2-a!1,2!diazepine-1-carboxylic acid, 1,1-dimethylethyl ester as a syrup. TLC(ethyl acetate:hexane, 1:1) R_(f) =0.28.

A solution of this material in dry methylene chloride was treated withanisole and trifluoroacetic acid according to the procedure of Example47 part (d) affording the title product as a solid; α!_(D) =-111.5°(c=0.48, methanol). TLC (ethyl acetate:acetic acid, 95:5) R_(f) =0.38.

g) 1S- 1α,8α(R*)!!-Hexahydro-8-(2-mercapto-1-oxo-3-phenylpropyl)amino!-9-oxo-1H,5H-pyrazolo 1,2-a!1,2!diazepine-1-carboxylic acid

A solution of the product from part (f) in dry methanol was treated with1.0N sodium hydroxide according to the procedure of Example 47 part (d)to give the title product as a white solid amorphous foam; α!_(D) =-71°(c=0.50, methanol). TLC (ethyl acetate:acetic acid, 95:5) R_(f) =0.25.

Anal calc'd. for C₁₈ H₂₃ N₃ O₄ S.0.13 C₅ H₁₂.0.20 H₂ O: C, 57.36; H,6.44; N, 10.76; S, 8.21; Found: C, 57.36; H, 6.50; N, 10.47; S, 8.10.

EXAMPLE 54 1S- 1α,8α(R*)!!-Hexahydro-8-(2-mercapto-1-oxo-3-phenylpropyl)amino!-5,9-dioxo-1H,5H-pyrazolor 1,2-a!1,2!diazepine-1-carboxylic acid

a) (1S-cis)-Hexahydro-8-amino-5,9-dioxo-1H,5H-pyrazolo 1,2-a!1,2!diazepine-1-carboxylic acid, 1,1-dimethylethyl ester

A solution of the product from Example 53 part (c) (700 mg., 1.67 mmol.)in absolute ethanol (7.4 ml.) was treated with hydrazine hydrate (0.19ml., 2.2 eq.) according to the procedure of Example 53 part (e) to give436 mg. of title product as a white foam. TLC (methylenechloride:methanol, 9:1) R_(f) =0.30.

b) 1S- 1α,8α(R*)!!-Hexahydro-8-(2-mercapto-1-oxo-3-phenylpropyl)amino!-5,9-dioxo-1H,5H-pyrazolo 1,2-a!1,2!diazepine-1-carboxylic acid

The product from part (a) was reacted with(S)-2-(acetythio)benzenepropanoic acid in the presence of triethylamineand benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate according to the procedure of Example 53 part (f)affording 1S- 1α,8α(R*)!!-hexahydro-8-2-(acetylthio)-1-oxo-3-phenylpropyl!amino!-5,9-dioxo-1H,5H-pyrazolo1,2-a! 1,2!diazepine-1-carboxylic acid, 1,1-dimethylethyl ester as asyrup. TLC (ethyl acetate:hexane, 1:1) R_(f) =0.22.

This material was treated with anisole followed by trifluoroacetic acidaccording to the procedure of Example 53 part (f). The resulting acidproduct was dissolved in methanol and treated with 1.0N sodium hydroxideaccording to the procedure of Example 53 part (g) affording the titleproduct as a white solid amorphous foam; α!_(D) =-95.8° (c=0.72,methanol). TLC (methylene chloride:methanol:acetic acid, 20:1:1) R_(f)=0.13.

Anal. calc'd for C₁₈ H₂₁ N₃ O₅ S.0.07 C₆ H₁₄.1.14 H₂ O: C, 52.89; H,5.83; N, 10.06; S, 7.67; Found: C, 52.89; H, 5.80; N, 9.18; S, 7.01.

EXAMPLE 55 3S- 1(R*),3α(R*),7β!!-Hexahydro-α-methyl-3-(2-mercapto-1-oxo-3-phenylpropyl!amino!-2-oxo-7-propyl-1H-azepine-1-aceticacid

a) 3S-1(R*),3α,7β!!-Hexahydro-α-methyl-3-phthalimido-2-oxo-7-(2-propenyl)-1H-azepine-1-aceticacid, methyl ester

Allyltrimethylsilane (1.53 ml., 9.6 mmol.) was added to a solution ofS-(R*,R*)!-hexahydro-α-methyl-3-phthalimido-2-oxo-1H-azepine-1-aceticacid, methyl ester (485 mg., 1.48 mmol.) in methylene chloride (20 ml.)at room temperature under argon. Following the addition of of stannicbromide (1.0M in methylene chloride, 2.52 ml., 2.52 mmol.), theresulting mixture was stirred for 4 hours. Another portion of stannicbromide (1.48 ml.) was added and stirring was continued for 48 hours.The reaction mixture was quenched with aqueous ammonium chloride andextracted with ethyl acetate. The organic layer was washed with brine,dried (sodium sulfate), filtered, and concentrated to give 1.2 g. of ayellow residue. The crude acid was dissolved in methanol, cooled to 0°C., and treated with diazomethane to generate the methyl ester. Thevolatiles were removed and the residue was flash chromatographed (Mercksilica gel) eluting with 1:3 ethyl acetate/hexane followed by 1:1 ethylacetate/hexane to give 283 mg. of title product as a white foam; α!_(D)=-13.7° (c=0.54, methylene chloride)). TLC(ethyl acetate:hexane, 1:1)R_(f) =0.50.

b) 3S-1(R*),3α,7β!!-Hexahydro-α-methyl-3-phthalimido-2-oxo-7-propyl-1H-azepine-1-aceticacid, methyl ester

A solution of the product from part (a) (463 mg., 1.24 mmol.) in 1:1methanol/ethyl acetate (14 ml.) was hydrogenated over 10% palladium oncarbon catalyst (41 mg.) for 3 hours. The mixture was filtered throughCelite and the volatiles were removed to give 483 mg. of title productas a yellow oil.

c) 3S- 1(R*),3α(R*),7β!!-Hexahydro-α-methyl-3-2-(acetylthio)-1-oxo-3-phenylpropyl!amino!-2-oxo-7-propyl-1H-azepine-1-aceticacid, methyl ester

The product from part (b) (483 mg.) was suspended in methanol (7 ml.) atroom temperature under argon. The mixture was treated with hydrazinemonohydrate (0.07 ml., 1.45 mmol.), became homogeneous, and was stirredfor 18 hours. The mixture was filtered to remove the white precipitateand the filtrate was stripped, treated with methylene chloride, filteredand stripped again to give 282 mg. of 3S-1(R*),3α,7β!!-hexahydro-α-methyl-3-amino-2-oxo-7-propyl-1H-azepine-1-aceticacid, methyl ester as a yellow oil.

(S)-2-(Acetylthio)benzenepropanoic acid (obtained from 491 mg. of thedicyclohexylamine salt as described previously) was dissolved inmethylene chloride (15 ml.) at room temperature under argon. Followingthe addition of the above amine (282 mg., 1.10 mmol.), the mixture wascooled to 0° C. and treated with triethylamine (0.17 ml., 1.21 mmol.)and benzotriazol-1-yloxytris (dimethylamino)phosphoniumhexafluorophosphate (511 mg., 1.16 mmol.) according to the procedure ofExample 36 part (f) to give 385 mg. of the title product as a whitefoam. TLC(ethyl acetate:hexane, 1:1) R_(f) =0.43.

d) 3S- 1(R*),3α(R*),7β!!-Hexahydro-α-methyl-3-(2-mercapto-1-oxo-3-phenylpropyl)amino!-2-oxo-7-propyl-1H-azepine-1-aceticacid

A solution of the product from part (c) (385 mg., 0.83 mmol.) inmethanol (10 ml.) was treated with 1N sodium hydroxide (8 ml.) accordingto the procedure of Example 36 part (g) to give 142 mg. of title productas a white powdery foam; α!_(D) =-51.6° (c=0.48, methylene chloride) TLC(1% acetic acid in 2:1 ethyl acetate/hexane) R_(f) =0.60.

Anal. calc'd. for C₂₁ H₃₀ N₂ O₄ S.0.14 H₂ O: C, 61.67; H, 7.46; N, 6.85;S, 7.84; Found: C, 61.97; H. 7.50; N, 6.55; S, 7.62.

EXAMPLE 56 S-(R*,R*)!-2,3,4,5-Tetrahydro-3-(2-mercapto-1-oxo-3-phenylpropyl)amino!-2-oxo-1H-pyrrolo 1,2-b!1,2!diazepine-1-acetic acid

a) S-(R*,R*)!-2,3,4,5-Tetrahydro-3-2-(acetylthio)-1-oxo-3-phenylpropyl!amino!-2-oxo-1H-pyrrolo 1,2-b!1,2!diazepine-1-acetic acid, ethyl ester

(S)-3-Amino-2-oxo-1H-pyrrolo 1,2-b! 1,2!diazepine-1-acetic acid, ethylester prepared as described by Bolos et al., J. Org. Chem., 57, p3535-33539 (1992)! was reacted with (S)-2-(acetylthio)benzenepropanoicacid in the presence of triethylamine andbenzotriazol-1-yloxytris-(dimethlamino)phosphonium hexafluorophosphateaccording to the procedure described above, as note Example 36 part (f),affording the title product as a colorless oil.

b) S-(R*,R*)!-2,3,4,5-Tetrahydro-3-(2-mercapto-1-oxo-3-phenylpropyl)amino!-2-oxo-1H-pyrrolo 1,2-b!1,2!diazepine-1-acetic acid

A solution of the product from part (a) (135 mg., 0.30 mmol.) inmethanol (2 ml.), tetrahydrofuran (1 ml.), and water (1 ml.) was spargedwith argon for 30 minutes. Lithium hydroxide monohydride (50 mg., 1.2mmol.) was added to the solution at room temperature. The reactionmixture was stirred for 2 hours with continuous argon sparge, thenacidified by the addition of 1M aqueous hydrochloric acid solution (1.4ml.), then added to water (20 ml.) and then extracted with ethyl acetate(2×15 ml.). The organic extracts were combined, dried (sodium sulfate),and concentrated in vacuo to give an oil. The crude material waspurified by flash chromatography (Merck silica, 12×1.5 cm., 1:99 aceticacid/ethyl acetate) to afford 115 mg. of title product as a white solidfoam; α!_(D) =-67° (c=0.26, methanol). TLC (aceticacid:methanol:methylene chloride, 1:10:90) R_(f) =0.43.

Anal. calc'd. for C₁₉ H₂₁ N₃ O₄ S: C, 58.90; H, 5.46; N, 10.85; S, 8.27;Found: C, 58.55; H, 5.50; N, 10.74; S, 8.17.

EXAMPLE 57 1S- 1α,9α(R*)!!-Octahydro-9-2-(methyldithio)-1-oxo-3-phenylpropyl!amino!-10-oxo-6H-pyridazino 1,2-a!1,2!diazepine-1-carboxylic acid

A solution of the product of Example 47 (100 mg., 0.247 mmol.) dissolvedin ethanol (1.5 ml.) and water (0.15 ml.) was cooled to 0° C. andtreated with methyl methanethiosulfonate (30.5 μl., 37.4 mg., 0.296mmol.). After 2 hours at 0° C. and 6 hours at room temperature, thereaction mixture was diluted with water and extracted with a mixture ofethyl acetate and ethyl ether. The organic extract was rinsed with waterand brine, dried (magnesium sulfate), and concentrated in vacuo to 157mg. of crude product. Flash chromatography on 12 g. of Merck silica geleluted with hexanes, then 1:1,hexanes:ethyl acetate, and finally4:4:0.05 followed by 4:4:0.1, hexanes:ethyl acetate:acetic acid yieldedpurified product. Trituration with ethyl acetate-hexanes afforded 85.4mg. of title product as a white solid foam; α!_(D) =-104.2° (c=0.18,chloroform). TLC(hexanes:ethyl acetate:acetic acid. 4:4:0:1) R_(f)=0.16.

Anal.calc'd.for C₂₀ H₂₇ N₃ O₄ S.0.05 C₄ H₈ O₂.0.01 C₆ H₁₄ : C, 54.95; H,6.27; N, 9.49; S, 14.48; Found: C, 55.03; H, 6.22; N, 9.49; S, 14.40.

EXAMPLE 58 S-((R*,R*)!-2,3,4,5-Tetrahydro-3-2-(methyldithio)-1-oxo-3-phenylpropyl!amino!-2-oxo-1H-benzazepine-1-aceticacid

A solution of the product of Example 6 (100 mg., 0.235 mmol.) dissolvedin ethanol (1.2 ml.) and water (0.112 ml.) was cooled to 0° C. andtreated with methyl methanesulfonate (29 μl., 35.6 mg., 0.282 mmol.).After one hour at 0° C., the reaction was kept at room temperature for 8hours, then refrigerated overnight. The reaction mixture was dilutedwith water and extracted with a mixture of ethyl acetate and ethylether. The organic extract was rinsed with water and brine, dried(magnesium sulfate), and concentrated in vacuo to 123 mg. of crudeproduct. Flash chromatography on 9 g. of Merck silica gel eluted withhexanes, then 1:1, hexanes:ethyl acetate, and finally 4:4:0.1,hexanes:ethyl acetate:acetic acid yielded 108 mg. of product.Trituration with ethyl acetate-hexanes gave 97 mg. of title product as awhite solid; m.p. 83°-95° C.; α!_(D) =-185.17° (c=0.3, chloroform).TLC(hexanes:ethyl acetate:acetic acid, 4:4:0.1) R_(f) =0.16.

Anal.calc'd. for C₂₂ H₂₄ N₂ O₄ S₂.0.84 H₂ O.0.07 C₄ H₈ O₂.0.07 C₆ H₁₄ :C, 57.78; H, 5.81; N, 5.94; S, 13.59; Found: C, 57.70; H, 6.13; N, 6.27;S, 13.20.

EXAMPLE 59 S-(R*,R*)!-2,3,4,5-Tetrahydro-3-(2-mercapto-1-oxo-4-methylpentyl)amino!-2-oxo-1H-benzazepine-1-aceticacid

a) (S)-2-Bromo-4-methylpentanoic acid

Potassium bromide (9.5 g., 80 mmol.) was added to a stirred solution ofD-leucine (3.0 g., 23 mmol.) in 2.5N sulfuric acid (47 ml.) at roomtemperature. The reaction mixture was cooled to -10° C. and solid sodiumnitrite (2.4 g., 34 mmol.) was added portionwise, maintaining thetemperature between -10° and -5° C. After addition was complete, thereaction was stirred for 1 hour and then warmed to room temperature andstirred for another hour. The reaction mixture was then extracted twicewith ether, the ether extracts were washed once with water, dried(magnesium sulfate), filtered and evaporated to give 2.7 g. of crudetitle product.

b) (S)-2-(Acetylthio)-4-methylpentanoic acid, dicyclohexylamine salt

To a stirred slurry of potassium thioacetate (1.7 g., 15.0 mmol.) in 50ml. of dry acetonitrile at room temperature under argon was added asolution of the product from part (a) (2.6 g., 13 mmol.) in 17 ml. ofacetonitrile. The reaction was stirred 4 hours. The resulting slurry wasfiltered and evaporated. The residue was redissolved in ethyl ether,washed once with 5% potassium hydrogen sulfate solution and once withbrine, dried (magnesium sulfate) and evaporated. The residue wasdissolved in ether (64 ml.) and treated with dicyclohexylamine (2.7 ml.,14 mmol.). A white solid immediately began precipitating from thesolution. The solution was filtered and the white solid collected togive 2.0 g. of title product; m.p. 153°-158° C.; α!_(D) =-54.5° C.(c=0.61, chloroform).

c) S-(R*,R*)!-2,3,4,5-Tetrahydro-3-2-(acetylthio)-1-oxo-4-methylpentyl!amino!-2-oxo-1H-benzazepine-1-aceticacid, ethyl ester

A stirred suspension of the product from part (b) (312 mg., 0.840 mmol.)in 5 ml. of ethyl acetate was washed twice with 5 ml. portions of 5%potassium hydrogen sulfate solution. The organic extract was dried(sodium sulfate), filtered, concentrated and dried in vacuo for 20minutes. The resulting oil was dissolved in 2.5 ml. of methylenechloride and stirred under argon at 0° C. To this solution was added asolution of (S)-2,3,4,5-tetrahydro-3-amino-2-oxo-1H-benzazepine-1-aceticacid, ethyl ester prepared as described by Watthey et al., J. Med.Chem., 28, p. 1511-1516 (1985)! (142 mg., 0.54 mmol.) in methylenechloride (3 ml.), then triethylamine (80 μl., 0.57 mmol.) and finallybenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(251 mg., 0.57 mmol.). After 1 hour, the reaction was warmed to roomtemperature and stirred 90 minutes. The resulting colorless solution wasevaporated at less than 30° C. and the oily residue redissolved in ethylacetate. The solution was washed once with 1M hydrochloric acid, oncewith water, once with a saturated solution of sodium bicarbonate andonce with brine. The organic layer was dried (magnesium sulfate),filtered and evaporated. Purification by flash chromatography (elutingwith 2:5 ethyl acetate/hexanes) provided 223 mg. of the title product;α!_(D) =-243.9° (c=0.62, chloroform).

d) S-(R*,R*)!-2,3,4,5-Tetrahydro-3-(2-mercapto-1-oxo-4-methylpentyl)amino!-2-oxo-1H-benzazepine-1-aceticacid

A solution of the product from part (c) (190 mg., 0.44 mmol.) in 4 ml.of methanol was purged with nitrogen for 5 minutes and cooled to 0° C.To this solution was added dropwise 4 ml. of nitrogen-purged 1M sodiumhydroxide. Nitrogen was slowly bubbled through the solution during thereaction. After one hour, the reaction was warmed to room temperatureand stirred one hour. The reaction was acidified with a 5% potassiumbisulfate solution and extracted with ethyl acetate, the extracts werewashed with water and a saturated solution of sodium chloride, dried(sodium sulfate) and evaporated. Reevaporation from hexanes yielded awhite solid. The solid was gently heated in ethyl ether, filtered toremove an insoluble oil, and crystallized with hexanes to give 117 mg.of title product as a white solid; m. p. 143°-144° C.; α!_(D) =-224.3°(c=0.46, chloroform). TLC (ethyl acetate/hexane/acetic acid, 4:4:0.1)R_(f) =0.19.

Anal. calc'd. for C₁₈ H₂₄ N₂ O₄ S.0.02 C₄ H₁₀ O: C, 59.34; H, 6.67; N,7.66; S, 8.76; Found: C, 58.97; H, 6.72; N, 7.52; S, 8.67.

EXAMPLE 60 R-(R*,S*)!-2,3,4,5-Tetrahydro-3-(2-mercapto-2-methyl-1-oxo-3-phenylpropyl)amino!-2-oxo-1H-benzazepine-1-aceticacid

a) S,S'-Bis(4-methoxy-α-toluenethiol)

A solution of 4-methoxy-α-toluenethiol (25 g., 0.16 mol.) in benzene(200 ml) was added to a solution of potassium carbonate (44.8 g., 0.32mol.) in water (200 ml.) and the resulting mixture was treatedportionwise, with rapid stirring, with iodine (23.6 g.) until the colorof iodine persisted. The reaction mixture was stirred for 15 minutesafter which the excess iodine was destroyed by the addition of solidsodium sulfite (10 g.). The reaction mixture was diluted with benzene(200 ml.) and partitioned, reextracting the aqueous phase with morebenzene (100 ml.). The combined organic extracts were washed with water(100 ml.), 5% sodium sulfite (100 ml.) and brine (50 ml.), dried(anhydrous magnesium sulfate), filtered, evaporated to dryness and driedin vacuo. The crude product was recrystallized from ethyl acetate (200ml.) and filtered, washing the cream colored precipitates with ethylacetate (25 ml.), to give 16.596 g. of title product; m. p. 99°-100° C.TLC(methylene chloride:methanol, 9:1) R_(f) =0.57.

b) α-Methyl-hydrocinnamic acid

A solution of α-methyl cinnamic acid (10.0 g., 61.7 mmol.) in drymethanol (250 ml.) was treated with 10% palladium on carbon andhydrogenated (balloon used) at room temperature for 16 hours. Thereaction mixture was diluted with methanol (250 ml.), filtered through aCelite pad in a millipore unit, washing the pad well with methanol(2×100 ml.). The clear filtrate was evaporated to dryness to give 10.225g. of title product as a thick syrup.

c) α-Methyl-α- (4-methoxyphenyl)methyl!thio!-hydrocinnamic acid

A solution of diisopropylamine (1.69 ml., 12.2 mmol.) in drytetrahydrofuran (9.0 ml.) was cooled to -30° C. (acetonitrile-dry icebath), treated with 2.5M butyllithium (4.84 ml., 12.1 mmol.) and stirredat -30° C. for 20 minutes. The resulting lithium diisopropylamidesolution was then treated with a solution of α-methyl-hydrocinnamic acid(1.0 g., 6.1 mmol.) in dry tetrahydrofuran (1.0 ml.), warmed up to roomtemperature and stirred under argon for 1.5 hours. The reaction mixturewas cooled to 0° C. (ice-salt bath), treated with a solution ofS,S'-bis(4-methoxy-α-toluenethiol) (1.869 g., 6.1 mmol.) in drytetrahydrofuran (6.0 ml) and stirred for 45 minutes at 0° C. underargon. The mixture was then added slowly to 1.0N hydrochloric acid (19.0ml.) and the aqueous mixture was extracted with ethyl acetate (2×50 ml).The combined organic extracts were washed with water (15 ml.) and brine(15 ml.), dried (anhydrous magnesium sulfate), filtered, evaporated todryness and dried in vacuo. The crude product mixture waschromatographed on a silica gel column (Merck), eluting the column withethyl acetate:hexane mixtures (1:4; 1:2) followed by ethylacetate:acetic acid (100:2) to give 1.45 g. of title product.

d) R-(R*,S*)!-2,3,4,5-Tetrahydro-3- 2-(4-methoxyphenyl)methyl!thio!-2-methyl-1-oxo-3-phenylpropyl!amino!-2-oxo-1H-benzazepine-1-aceticacid, 1,1-dimethylethyl ester and S-(R*,R*)!-2,3,4,5-tetrahydro-3- 2-(4-methoxyphenyl)-methyl!thio!-2-methyl-1-oxo-3-phenylpropyl!amino!-2-oxo-1H-benzazepine-1-aceticacid, 1,1-dimethylethyl ester

A solution of the product from part (c) (497 mg., 1.57 mmol., 1.09 eq.)was cooled to 0° C. (ice-salt bath), treated with a solution of(S)-2,3,4,5-tetrahydro-3-amino-2-oxo-1H-benzazepine-1-acetic acid,1,1-dimethylethyl ester prepared according to the procedure of Wattheyet al., J. Med. Chem. 28, p. 1511-1516 (1985)! (417 mg., 1.44 mmol.) indry methylene chloride (2.9 ml.) followed by triethylamine (0.2 ml.,1.45 mmol.) and benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (642 mg., 1.45 mmol.). The reaction mixture wasstirred at 0° C. for 1.0 hour then at room temperature for 2.5 hoursafter which it was evaporated to dryness. The syrup obtained wasredissolved in ethyl acetate (50 ml.) and the resulting solution washedwith 0.5N hydrochloric acid (2×8.3 ml.), water (8.3 ml.) and brine (8.3ml.), dried (anhydrous sodium sulfate), filtered, evaporated to drynessand dried in vacuo. The crude product was chromatographed on a silicagel column (Merck), eluting the column with ethyl acetate:hexane (1:4)to give 709 mg. of a mixture of isomeric products.

Rechromatography of the isomer mixture on a silica gel column andelution with ethyl acetate:methylene chloride (1:99, 2:98) gave 340 mg.of the R-(R*,S*)! title product; α!_(D) =-72° (c=0.66, methanol);TLC(ethyl acetate:hexane, 1:1) R_(f) =0.70 and 316 mg. of theS-(R*,R*)title product; α!_(D) =-142° (c=0.5, methanol); TLC(ethylacetate:hexane, 1:1) R_(f) =0.87.

e) R-(R*,S*)!-2,3,4,5-Tetrahydro-3-(2-mercapto-2-methyl-1-oxo-3-phenylpropyl)amino!-2-oxo-1H-benzazepine-1-aceticacid

A solution of the R-(R*,S*)! product from part (d) (300 mg., 0.51 mmol.)in trifluoroacetic acid (2.5 ml.) was cooled to 0° C. (ice-salt bath),treated with anisole (0.25 ml., 2.3 mmol.) and trifluoromethanesulfonicacid (0.13 ml., 1.47 mmol.) and stirred at 0° C. for 2.5 hours underargon. The reaction mixture was stripped to dryness, evaporating theresidual syrup from ethyl acetate (2×15 ml.) then dried in vacuo. Thecrude product mixture was chromatographed on a silica gel column(Merck), eluting the column with ethyl acetate and ethyl acetate:aceticacid (100:2). The first set of desired fractions were combined andpartitioned between ethyl acetate and 1.0N hydrochloric acid to give91.0 mg. of crude product. This was combined with a second set offractions which were also rechromatographed separately on another silicagel column to give a total amount of 301 mg. which still had impurities.Rechromatography on a third silica gel column was done, eluting thecolumn with toluene:acetic acid (6:1) to give 156 mg. of pure titleproduct as a solid foam; α!_(D) =-248.3° (c=0.73, methanol).TLC(toluene:acetic acid, 5:1) R_(f) =0.28.

Anal. calc'd. for C₂₂ H₂₄ N₂ O₄ S.0.21 C₆ H₁₄.0.54 H₂ O: C, 63.82; H,5.85; N, 6.40; S, 7.32; Found: C, 63.82; H, 6.14; N, 6.21; S, 7.16.

EXAMPLE 61 S-(R*,R*)!-2,3,4,5-Tetrahydro-3-(2-mercapto-2-methyl-1-oxo-3-phenylpropyl)amino!-2-oxo-1H-benzazepine-1-aceticacid

A solution of the (S-(R*,R*)! product from Example 60 part (d) (316 mg.,0.54 mmol.) in trifluoroacetic acid (2.63 ml.) was cooled to 0° C. andtreated with anisole (0.26 ml., 2.30 mmol.) and trifluoromethanesulfonicacid (0.14 ml., 1.58 mmol.) according to the procedure of Example 60part (e) to give 209.8 mg. of title product; α!_(D) =-123° (c=0.48,methanol). TLC (toluene:acetic acid, 5:1) R_(f) =0.35.

Anal. calc'd. for C₂₂ H₂₄ N₂ O₄ S.0.4 C₆ H₁₄ : C, 64.22; H, 5.95; N,6.73; S, 7.70; Found: C, 64.38; H, 6.19; N, 6.27; S, 7.05.

EXAMPLE 62 3R- 3α,6α(s*),9aβ!!-Octahydro-6-(2-mercapto-1-oxo-3-phenylpropyl)amino!-5-oxothiazolo3.2-alazepine-3-carboxylic acid, 1-oxide

a) 3R- 3α,6α(S*),9αβ!!-Octahydro-6-2-(acetylthio)-1-oxo-3-phenylpropyl!amino!-5-oxothiazolo3,2-alazepine-3-carboxylic acid, 1-oxide, methyl ester

A solution of the product from Example 11 part (f) (301 mg., 0.67 mmol.)in chloroform (9.5 ml.) was cooled to 0°-5° C. To this solution wasadded a solution of meta-chloroperoxybenzoic acid (137 mg., 0.79 mmol.)in chloroform (7 ml.). The reaction mixture was stirred at 0° C. undernitrogen. After 1 hour, TLC showed the absence of starting material. Thereaction mixture was diluted with chloroform (66 ml.), washed withdilute sodium bicarbonate (2×13 ml.) (pH=10), water (27 ml.) and driedover sodium sulfate. It was filtered and concentrated in vacuo to afoamy solid. The foamy solid was flash chromatographed over Merck silicagel (30 ml.) with ethyl acetate:acetonitrile (95:5) (400 ml.) to give263 mg. of title product as a 55:45 mixture of diastereomers (R,Smixture of sulfoxide). TLC(ethyl acetate:acetonitrile, 95:5) R_(f)=0.23.

b) 3R- 3α,6α(s*)9aβ!!-Octahydro-6-(2-mercapto-1-oxo-3-phenylpropyl)amino!-5-oxothiazolo3,2-alazepine-3-carboxylic acid, 1-oxide.

A solution of the product from part (a) (263 mg., 0.56 mmol.) inmethanol (3.4 ml., deoxygenated via argon bubbling) was treated with 1Nsodium hydroxide (2.8 ml., 2.8 mmol., deoxygenated via argon bubbling)and the clear solution was stirred under argon at room temperature.After 2 hours, TLC showed the absence of starting material. The solutionwas acidified with 10% potassium bisulfate (12.5 ml.), diluted withwater (17 ml.), and extracted with ethyl acetate (3×60 ml.). The ethylacetate extract was washed with water (25 ml.), brine (50 ml.) and driedover sodium sulfate. It was filtered and concentrated to an oilyresidue. Treatment of this residue with hexane and ethyl ether gave asolid (230 mg.). The solid was flash chromatographed over Merck silicagel (50 ml.), using ethyl acetate/acetonitrile/acetic acid (50:50:6to7)(600 ml.) to give (142 mg.) of solid. The solid (142 mg.) was dissolvedin methanol (2 ml.) and diluted with ethyl acetate (25 ml.). It waswashed with 10% potassium bisulfate (3 ml.)(pH=2), diluted with water (8ml.). The organic layer was separated. The aqueous layer was extractedwith ethyl acetate (3×10 ml.). The combined ethyl acetate extract waswashed with water (5 ml.), brine (5 ml.), dried over sodium sulfate,filtered and concentrated to an oily residue. Trituration of thisresidue with ethyl acetate/ethyl ether gave 102 mg. of title product asa single isomer; m.p. 129°-132° C. (foaming); α!_(D) =-89.3° (c=0.3,dimethylformamide). TLC(ethyl acetate/acetonitrile/acetic acid) R_(f)=0.26.

Anal. calc'd. for C₁₈ H₂₂ N₂ O₅ S₂.0.12 C₄ H₈ O₂.0.56 H₂ O: C, 51.48; H,5.62; N,6.49; S,14.87; Found: C, 51.32; H, 5.34; N,6.74; S,14.50.

EXAMPLE 63 3S- 3α(R*),7α!!-Hexahydro-3-(2-mercapto-1-oxo-3-phenylpropyl)amino!-2-oxo-7-propyl-1H-azepine-1-aceticacid

a) (S)-2-Phthalimido-6-hydroxyhexanoic acid, phenylmethyl ester

A slurry of cesium carbonate (3.819 g, 11.7 mmol.) and(S)-2-phthalimido-6-hydroxyhexanoic acid (6.00 g, 21.6 mmol.) indimethylformamide (60 ml.) was treated with benzyl bromide (3.30 ml.,4.75 g., 27.7 mmol.). After stirring at room temperature for 2 hours,the mixture was partitioned between ethyl acetate and water. The organicextract was washed with water (twice) and brine, then dried (sodiumsulfate), filtered and stripped to give an oil. The oil was flashchromatographed (Merck silica gel, 6/4-ethyl acetate/hexane) to giveessentially pure product as a solid. Recrystallization from ethylacetate/hexane gave 7.173 g. (1st crop) and 394 mg. (2nd crop) for atotal of 7.567 g. of pure title product; m.p. 106°-108.5° C.; α!_(D)=-27.5° (c=1.5, methanol). TLC (75/25 ethyl acetate/hexanes) R_(f)=0.43.

b) (S)-2-Phthalimido-6-oxohexanoic acid, phenylmethyl ester

A -78° C. solution of oxalyl chloride (2.0 ml., 2.91 g., 22.9 mmol.) indry methylene chloride (180 ml.) was treated dropwise with a solution ofdry dimethylsulfoxide (3.20 ml., 3.52 g., 45.1 mmol.) in methylenechloride (3 ml.). After 15 minutes, a solution of the product from part(a) (6.874 g., 18.7 mmol.) in methylene chloride (20 ml.) was added.After an additional 15 minutes, triethylamine (15.0 ml.) was added andthe mixture was stirred at -78° C. for 5 minutes, then allowed to warmto 0° C. The mixture was diluted with ethyl ether and was subsequentlywashed with water, 1N hydrochloric acid, and brine, then dried (sodiumsulfate), filtered and stripped. The residue was flash chromatographed(Merck silica gel, 4/6-ethyl acetate/hexanes) to give 6.87 g. of titleproduct as a colorless oil. TLC (1:1, ethyl acetate:hexanes) R_(f)=0.43.

c) (2S)-2-Phthalimido-6-hydroxy-8-nonenoic acid, phenylmethyl ester

A cold (0° C.) solution of the product from part (b) (6.249 g., 17.1mmol.) and allyl trimethylsilane (3.40 ml., 2.44 g., 21.4 mmol.) in drymethylene chloride (120 ml.) was treated with titanium tetrachloride(1.0M in methylene chloride, 18.8 ml., 18.8 mmol.) over a 2 minuteperiod. After 30 minutes, the bright yellow solution was quenched withwater and partitioned between ethyl acetate and saturated ammoniumchloride. The ethyl acetate extract was washed with water and brine,dried (sodium sulfate), filtered and stripped to give a cloudy oil. Theresidue was flash chromatographed (Merck silica gel, 15/85-ethylacetate/methylene chloride) to afford 6.40 g., of title product as a 1:1mixture of diastereomers. TLC (1:4, ethyl acetate:methylene chloride)R_(f) =0.52.

d) (2S)-2-Phthalimido-6-azido-8-nonenoic acid, phenylmethyl ester

A solution of the product from part (c) (6.365 g., 15.6 mmol.) indimethylformamide (120 ml.) at room temperature was treated with lithiumazide (4.620 g., 94.4 mmol.) and bromotrichloromethane (4.60 ml., 9.26g., 46.7 mmol.). The bright yellow solution was then treated withtriphenylphosphine (10.242 g., 39.0 mmol.). The mixture became darkorange and a water bath was necessary in order to cool the slightlyexothermic reaction. After 2 hours at room temperature, the reaction wasquenched with saturated sodium bicarbonate and extracted with ethylacetate/ethyl ether. The organic layer was washed with water (3 times)and brine, dried (sodium sulfate), filtered and stripped. The residuewas flash chromatographed (Merck silica gel, 5/95-ethylacetate/methylene chloride) to afford partially purified product. Thismaterial was rechromatographed (Merck silica gel, 1/9-hexanes/methylenechloride) to give essentially pure title product as a yellow oil. TLC(5:95, ethyl acetate:methylene chloride) R_(f) =0.63.

e) (3S-trans)-Hexahydro-3-phthalimido-7-propyl-2H-azepin-2-one and(3S-cis)-hexahydro-3-phthalimido-7-propyl-2H-azepin-2-one

The product from part (d) (4.27 g., 9.87 mmol.) was hydrogenated(balloon) in dimethylformamide (100 ml.) over palladium (10% on carbon,1.8 g.) for 42 hours. The solution was filtered through Celite® and thefiltrate was treated with hydroxybenzotriazole (1.366 g., 10.1 mmol.)followed by ethyl-3-(dimethylamino)propyl carbodiimide, (1.987 g., 10.4mmol.). After stirring at room temperature for 5 hours, the mixture waspartitioned between ethyl acetate and 0.5N hydrochloric acid, and theorganic layer was washed successively with water, 50% saturated sodiumbicarbonate, and brine, then dried (sodium sulfate), filtered andstripped to give an orange oil. Initial purification of the oil (flashchromatography, Merck silica gel, 6/4-ethyl acetate/hexanes) yielded apartially separated mixture of the (3S-trans) and (3S-cis) products(1.519 g. total of both). Repeated flash chromatography (Merck silicagel, 6/4-ethyl acetate/hexanes) and recrystallization permitted thequantitative isolation of 774 mg. of(3S-cis)-hexahydro-3-phthalimido-7-propyl-2H-azepin-2-one, m.p.155°-175° C. (very broad); α!_(D) =+55.7° (c=0.7, chloroform). TLC(75/25, ethyl acetate/hexane) R_(f) =0.48.

An analytical sample of(3S-trans)-hexahydro-3-phthalimido-7-propyl-2H-azepin-2-one was alsoobtained; m.p. 146°-151° C. TLC (75/25 ethyl acetate/hexanes) R_(f)=0.38.

f) (3S-cis)-Hexahydro-3-(1,1-dimethylethoxy)-carbonyl!amino!-7-propyl-2H-azepin-2-one

A solution of the (3S-cis)product from part (e) (758 mg., 2.52 mmol.) inmethylene chloride (4 ml.) and methanol (8 ml.) was treated withhydrazine monohydrate (147 μl., 152 mg., 3.0 mmol.). After 1 houradditional hydrazine monohydrate (50 μl.) was added and stirringcontinued for 4 days. The resulting thick slurry was diluted withadditional methanol and methylene chloride and was subsequentlyfiltered. The filtrate was stripped, slurried in methylene chloride,filtered and stripped again to afford the crude amine as an oil. The oilwas dissolved in chloroform (5 ml.) and treated in succession withtriethylamine (350 μl., 254 mg., 2.5 mmol.) and di-tert-butyldicarbonate (660 mg., 3.0 mmol.). After stirring at room temperature for2 hours, the solvent was stripped and the residue was flashchromatographed (Merck silica gel, 2/8-ethyl acetate/methylene chloride)to give 609 mg. of title product as a solid; m.p. 114.4°-115.5° C.;α!_(D) =+28.7° (c=0.5, chloroform). TLC (25/75 ethyl acetate/methylenechloride) R_(f) =0.37.

g) (3S-cis)-Hexahydro-3-(1,1-dimethylethoxy)-carbonyl!amino!-7-propyl-1H-azepine-1-acetic acid,ethyl ester

A room temperature solution of the product from part (f) (539 mg., 1.99mmol.) in dry tetrahydrofuran (20 ml.) was treated dropwise with lithiumhexamethyldisilazide (1.0M in tetrahydrofuran, 2.60 ml., 2.60 mmol.)followed 30 seconds later with ethyl bromoacetate (450 μl., 678 mg.,4.06 mmol.). The mixture was stirred at room temperature for 45 minutes,then quenched with saturated ammonium chloride, diluted with water, andextracted with ethyl acetate. The ethyl acetate extract was washed withbrine, dried (sodium sulfate), filtered and stripped to give an oil.Flash chromatography (Merck silica gel, 35/65-ethyl acetate/hexane)afforded 620 mg. of pure title product as an oil. TLC (1:1 ethylacetate/hexane) R_(f) =0.55.

h) 3S-{3α(R*),7α!!-Hexahydro-3-2-(acetylthio)-1-oxo-3-phenylpropyl!amino!-2-oxo-7-propyl-1H-azepine-1-aceticacid, ethyl ester

A solution of the product from part (g) (700 mg., 1.96 mmol.) inp-dioxane (3 ml.) was treated with hydrochloric acid (4.0M in p-dioxane,6.3 ml.). The mixture was stirred at room temperature for 2 hours. Thesolvent was stripped and the residue was partitioned between ethyl etherand 0.2N sodium hydroxide (13 ml.). The layers were separated and theaqueous layer was extracted with ethyl acetate. The pooled organicextracts were dried (sodium sulfate), filtered and stripped to give 462mg. of the crude free amine as a pale yellow oil.

A solution of (S)-(acetylthio)benzenepropanoic acid (obtained from thedicyclohexylamine salt as described previously, 485 mg., 2.16 mmol.) andthe above crude amine in methylene chloride (15 ml.) was treated withtriethylamine (300 μl., 218 mg., 2.15 mmol.) and the mixture was cooledto 0° C. Benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate (956 mg., 2.16 mmol.) was then added as a solid. Thesolution was stirred at 0° C. for 1 hour and then at room temperaturefor 1.5 hours. The solvent was stripped and the residue was partitionedbetween ethyl acetate and 0.5N hydrochloric acid. The organic layer waswashed successively with water, 50% saturated sodium bicarbonate andbrine, then dried (sodium sulfate), filtered and stripped. The residuewas flash chromatographed (Merck silica gel, 4:6-ethyl acetate:hexanes)to give 685 mg. of title product as an oil. TLC (1:1, ethylacetate:hexanes) R_(f) =0.37.

i) 3S- 3α(R*),7α!!-Hexahydro-3-(2-mercapto-1-oxo-3-phenylpropyl)amino!-2-oxo-7-propyl-1H-azepine-1-aceticacid

A room temperature solution of the product from part (h) (679 mg., 1.47mmol.) in methanol (10 ml., deoxygenated via argon bubbling) was treatedwith 1N sodium hydroxide (10 ml., deoxygenated via argon bubbling).After stirring for 30 minutes, the solution was acidified with 10%hydrochloric acid and extracted with ethyl acetate. The ethyl acetateextract was washed with water and brine, then dried (sodium sulfate),filtered and stripped. The residue was flash chromatographed (Mercksilica gel, ethyl acetate followed by 1.5% acetic acid in ethylacetate). The fractions containing pure product were pooled, stripped,and azeotroped twice with ethyl acetate. The mixture was dissolved in asmall amount of ethyl acetate and triturated with hexane to give a foam.The volatiles were stripped, the residue was slurried in hexane,stripped to dryness again, and dried in vacuo to give 573 mg. of titleproduct as a relatively hard white foam; α!_(D) =+7.6 (c=0.8,chloroform). TLC (2% acetic acid in ethyl acetate) R_(f) =0.47.

Anal. calc'd. for C₂₀ H₂₈ N₂ O₄ S.0.26 H₂ O: C, 60.47; H, 7.24; N, 7.05;S, 8.07; Found: C, 60.73; H, 7.38; N, 6.79; S, 7.76.

EXAMPLE 64 3S- 3α(R*), 7β!!-Hexahydro-3-(2-mercapto-1-oxo-3-phenylpropyl)amino!-7-methyl-2-oxo-1H-azepine-1-aceticacid

a) (S)-2-Phthalimido-6-hydroxyhexanoic acid, methyl ester

A slurry of (S)-2-phthalimido-6-hydroxyhexanoic acid (3.752 g., 13.5mmol.) and cesium carbonate (2.178 g., 6.7 mmol.) in dimethylformamide(44 ml.) was treated with methyl iodide (3.0 ml., 6.84 g., 48.2 mmol.).After stirring at room temperature for 2 hours, the mixture was dilutedwith ethyl acetate and washed successively with water containing a smallamount of sodium bisulfite, water, 50% saturated sodium bicarbonate, andbrine, then dried (sodium sulfate), filtered and stripped to give thetitle product as a colorless oil (3.825 g.). The oil was homogeneous byTLC (1:1-acetone:hexanes) R_(f) =0.37.

b) (S)-2-Phthalimido-6-oxohexanoic acid, methyl ester

A solution of oxalyl chloride (2.76 ml.) in methylene chloride (150 ml.)at -78° C. under argon was treated with the dropwise addition ofdimethylsulfoxide (4.41 ml.) in methylene chloride (18 ml.). After 15minutes, a solution of the product from part (a) (7.77 g., 25.1 mmol.)in methylene chloride (20 ml.) was added and the resulting mixture wasstirred for 15 minutes. Following the addition of triethylamine (18.7ml.)., the mixture was stirred for 10 minutes then warmed to roomtemperature. The mixture was diluted with ethyl acetate then partitionedwith water. The organic layer was washed with 1N hydrochloric acid andbrine, dried over sodium sulfate, filtered and concentrated. The yellowresidue was flash chromatographed (E Merck silica gel) eluting with 2:3ethyl acetate/hexanes to give 6.47 g. of title product as as a yellowoil. TLC (1:1 ethyl acetate:hexane) R_(f) =0.47.

c) (2S)-2-Phthalimido-6-hydroxyheptanoic acid, methyl ester

A solution of the product from part (b) (6.4 g., 22.15 mmol.) inmethylene chloride (150 ml.) at room temperature under argon was cooledto 0° C. and treated with 14.4 ml. of 2M trimethylaluminum in hexanes(28.8 mmol.). After stirring for 1 hour, the mixture was carefullyquenched with saturated aqueous ammonium chloride and partitionedbetween ethyl acetate and 1N hydrochloric acid. The organic layer waswashed with brine, dried (sodium sulfate), filtered and concentrated togive 7.4 g. of title product as a light yellow oil. TLC (1:1 ethylacetate:hexane) Rf=0.30.

d) (2S)-2-Phthalimido-6-azidoheptanoic acid, methyl ester

To a solution of the product from part (c) (7.1 g., 21 mmol.) indimethylformamide (45 ml.) at room temperature under argon was addedsodium azide (4.93 g., 75.8 mmol.) followed by trichlorobromomethane(6.3 ml., 63.0 mmol.) and then triphenylphosphine (13.77 g., 52.5mmol.). The resulting mixture was stirred 2.5 hours then partitionedbetween ethyl acetate and saturated aqueous sodium bicarbonate. Theorganic layer was washed with water and brine, dried (sodium sulfate),filtered and concentrated. The residue was flash chromatographed (EMerck silica gel) eluting with 20% ethyl acetate in methylene chlorideto give 10 g. of product contaminated with other impurities. This wasresubjected to flash chromatography eluting with 4:1 hexane/ethylacetate to give 6.7 g. of title compound as a yellow oil. TLC (1:1 ethylacetate:hexane) Rf=0.60.

e) (2S)-2- (1,1-Dimethylethoxy)carbonyl!amino!-6-azidoheptanoic acid,methyl ester

Hydrazine monohydrate (1.05 ml., 21.74 mmol.) was added to a solution ofthe product from part (d) (6.7 g., 19.8 mmol.) in methanol (50 ml.) atroom temperature under argon. The resulting mixture was stirred for 96hours then filtered to remove the formed white precipitate. Thevolatiles were evaporated and the residue was dissolved in methylenechloride and filtered to remove additional precipitate. The volatileswere evaporated and the residue was partitioned between ethyl ether and0.5M aqueous hydrochloric acid. The aqueous layer was basified withaqueous sodium bicarbonate and extracted eight times with methylenechloride. The combined organic layers were dried (sodium sulfate),filtered, and concentrated to give 2.9 g. of the free amine as a yellowoil. This amine intermediate (2.9 g., 14.5 mmol.) was dissolved inmethylene chloride (10 ml.), treated with triethylamine (2.02 ml., 14.5mmol.), and stirred for 5 minutes. Di-tert-butyl dicarbonate (3.8 g.,17.44 mmol.) was added and the resulting mixture was stirred for 45minutes. Additional di-tert-butyl dicarbonate (0.63 g.) was added andthe mixture was stirred for 30 minutes. The mixture was diluted withmethylene chloride and washed twice with water, dried (sodium sulfate),filtered and concentrated to a yellow oil. The oil was flashchromatographed (E Merck silica gel) eluting with 4:1 hexanes/ethylacetate to give 3.34 g. of title compound as a yellow oil. TLC (4:1hexanes:ethyl acetate) Rf=0.60.

f) (3S-trans)-Hexahydro-3-(1,1-dimethylethoxy)carbonyl!amino!-7-methyl-2H-azepinn-2-one and(3S-cis)-hexahydro-3-(1,1-dimethylethoxy)-carbonyl!amino!-7-methyl-2H-azepin-2-one

To a solution of the product from part (e) (2.8 g., 9.3 mmol.) inmethanol (125 ml.) was added 1.0 g. of 10% palladium on carbon at roomtemperature. The resulting mixture was hydrogenated (balloon) for 28hours and then filtered through Celite® to remove the catalyst. Thevolatiles were evaporated and the residue was azeotroped twice withchloroform to ensure the complete removal of methanol. The free aminewas dissolved in methylene chloride (125 ml.) then treated with 2Mtrimethylaluminum in hexanes (8.8 ml., 17.52 mmol.). The resultingmixture was stirred at room temperature under argon for 27 hours. Themixture was quenched with saturated aqueous ammonium chloride andextracted with ethyl acetate. The organic layer was washed with brine,dried (sodium sulfate), filtered and concentrated. The residue was flashchromatographed (E Merck silica gel) eluting with 1:1 ethylacetate/hexanes to give a clean separation of 452 mg. of the more polarisomer (3S-trans)-hexahydro-3-(1,1-dimethylethoxy)carbonyl!amino!-7-methyl-2H-azepine-2-one; m.p.137°-138° C.; α!_(D) =-2.8° (c=0.82, methylene chloride); TLC (1:1 ethylacetate:hexane) R_(f) =0.23 and 550 mg. of the less polar isomer(3S-cis)-hexahydro-3-(1,1-dimethylethoxy)carbonly!amino!-7-methyl-2H-azepin-2-one; m.p.108°-109° C.; α!_(D) =+18.1° (c=0.27, methylene chloride); TCL (1:1ethyl acetate:hexane) R_(f) =0.39.

g) (3S-trans)-Hexahydro-3- (1,1-dimethyl-ethoxy)carbonyl!amino!-7-methyl-2-oxo-1H-azepine-1-acetic acid, ethyl ester.

A solution of (3S-trans)-hexahydro-3-(1,1-dimethylethoxy)carbonyl!aminio!-7-methyl-2H-azepin-2-one (313 mg.,1.3 mmol.) in tetrahydrofuran (8 ml.) at room temperature under argonwas treated with the dropwise addition of 1.0M lithiumbis(trimethylsilyl) amide in tetrahydrofuran (1.7 ml., 1.7 mmol.)immediately followed by the dropwise addition of ethyl bromoacetate(0.30 ml., 2.65 mmol.). The resulting mixture was stirred for 15minutes, quenched with aqueous ammonium chloride, diluted with water andextracted twice with ethyl acetate. The combined organic layers werewashed with brine, dried (sodium sulfate), filtered and concentrated toa yellow oil. Following flash chromatography (E Merck silica gel)eluting with 2:1 hexane/ethyl acetate, 360 mg. of title compound wasobtained as a light yellow oil; TLC (1:1 ethyl acetate:hexane) R_(f)=0.56.

h) 3S- 3α (R*), 7β!!-Hexahydro-3-2-(acetylthio)-1-oxo-3-phenylpropyl!amino!-7-methyl-2-oxo-1H-azepine-1-aceticacid, ethyl ester

A solution of the product from part (g) (296 mg., 0.90 mmol.) inp-dioxane (2 ml.) was treated with 4.0M hydrochloric acid in dioxane(2.9 ml.) at room temperature under argon. After stirring for 6 hours,the volatiles were evaporated and the residue was partitioned betweenethyl acetate and half saturated aqueous sodium bicarbonate. The aqueouslayer was back-extracted with ethyl acetate and the combined organiclayers were washed with brine, dried (sodium sulfate), filtered, andconcentrated to give the deprotected amine as a yellow oil.

(S)-(Acetylthio)benzenepropanoic acid, dicyclohexylamine salt (405.6mg., 1.0 mmol.) was partitioned between ethyl acetate and 10% potassiumbisulfate. The organic layer was washed with brine, dried (sodiumsulfate), filtered, and concentrated to give the free acid(S)-(acetylthio)benzenepropanoic acid as an oil. This oil was dissolvedin methylene chloride (15 ml.) at room temperature under argon.Following the addition of the above deprotected amine, the mixture wascooled to 0° C. and triethylamine (0.12 ml.) was added. The resultingmixture was stirred for 5 minutes thenbenzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate(442 mg., 1.0 mmol.) was added. After stirring at 0° C. for 1 hour, thereaction mixture was warmed to room temperature and was stirred for 16hours. The volatiles were evaporated and the residue was dissolved inethyl acetate and washed successively with 1N hydrochloric acid, water,50% saturated sodium bicarbonate, and brine. The organic layer was dried(sodium sulfate), filtered, and concentrated and the residue was flashchromatographed (E Merck silica gel) eluting with 2:1 hexane/ethylacetate to give 260 mg. of title product as a pale yellow oil; TLC (2:1hexane:ethyl acetate) Rf=0.43.

i) 3S- 3α(R*),7β!!-Hexahydro-3-(2-mercapto-1-oxo-3-phenylpropyl)amino!-7-methyl-2-oxo-1H-azepine-1-aceticacid

A solution of the product from part (h) (255 mg., 0.63 mmol) in methanol(8 ml., deoxygenated via argon bubbling) was cooled to 0° C. and treatedwith 1N sodium hydroxide (6 ml., deoxygenated via argon bubbling). Afterstirring under argon at 0° C. for 30 minutes, the resulting mixture waswarmed to room temperature and stirred an additional hour. The mixturewas acidified with 10% potassium bisulfate and extracted with ethylacetate. The organic layer was washed successively with water and brine,dried (sodium sulfate), filtered and concentrated to give a yellow oil.This residue was flash chromatographed (E Merck silica gel) eluting with1% acetic acid in 1:2 hexane/ethyl acetate. The fractions containingclean desired product were combined, stripped, azeotroped with ethylacetate, and washed with water to remove any acetic acid. The organiclayer was dried (sodium sulfate), filtered and concentrated. The residuewas taken up in ethyl acetate and triturated with hexane. The solventwas removed and the residue was slurried in hexane, stripped, and driedin vacuo to give 120 mg. of title product as a white powdery foam;α!_(D) =-28.7° (c=0.30, methanol). TLC (1% acetic acid in 2:1 ethylacetate/hexane) R_(f) =0.40.

Anal. calc'd. for C₁₈ H₂₄ N₂ O₄ S: C, 59.32; H, 6.64; N, 7.69; S, 8.80;Found: C, 59.03; H, 6.76; N, 7.36; S, 8.58.

EXAMPLE 65 3S- 3α(R*),7α!!-Hexahydro-3-(2-mercapto-1-oxo-3-phenylpropyl)amino!-7-methyl-2-oxo-1H-azepine-1-aceticacid

a) (3S-cis)-Hexahydro-3-(1,1-dimethylethoxy)-carbonyl!amino!-7-methyl-2-oxo-1H-azepine-1-aceticacid, ethyl ester

A solution of (3S-cis)-hexahydro-3-(1,1-dimethylethoxy)carbonyl!amino!-7-methyl-2H-azepin-2-one prepared asdescribed in Example 64(f), 500 mg., 2.06 mmol.! in tetrahydrofuran (13ml.) at room temperature under argon was treated dropwise with 1.0Mlithium bis(trimethylsilyl)amide in tetrahydrofuran (2.7 ml., 2.7 mmol.)immediately followed by the dropwise addition of ethyl bromoacetate(0.47 ml., 4.21 mmol.). The resulting mixture was stirred for 30minutes, quenched with aqueous ammonium chloride, diluted with water andextracted twice with ethyl acetate. The combined organic layers werewashed with brine, dried (sodium sulfate), filtered and concentrated toa yellow oil. Following flash chromatography (E Merck silica gel)eluting with 2:1 hexane/ethyl acetate, 750 mg. of title product wasobtained as a light yellow oil; TLC (1:1 ethyl acetate:hexane) R_(f)=0.52.

b) 3S- 3α(R*),7α!!-Hexahydro-3-2-(acetylthio)-1-oxo-3-phenylpropyl!amino!-7-Methyl-2-oxo-1H-azepine-1-aceticacid, ethyl ester

A solution of the product from part (a) (351 mg., 1.07 mmol.) inp-dioxane (3 ml.) was treated with 4.0M hydrochloric acid in dioxane(3.45 ml.) at room temperature under argon. After stirring for 2 hours,the volatiles were evaporated and the residue was partitioned betweenethyl acetate and 50% saturated aqueous sodium bicarbonate. The aqueouslayer was back-extracted with ethyl acetate and the combined organiclayers were washed with brine, dried (sodium sulfate), filtered, andconcentrated to give the deprotected amine as a yellow oil.

(S)-(Acetylthio)benzenepropanoic acid, dicyclohexylamine salt (477 mg.,1.18 mmol.) was partitioned between ethyl acetate and 10% potassiumbisulfate. The organic layer was washed with brine, dried (sodiumsulfate), filtered, and concentrated to give(S)-(acetylthio)benzenepropanoic acid as an oil. This oil was dissolvedin methylene chloride (15 ml.) at room temperature under argon.Following the addition of the above deprotected amine, the mixture wascooled to 0° C. and triethylamine (0.14 ml.) was added. The resultingmixture was stirred for 5 minutes, then benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (522 mg., 1.8 mmol.) wasadded. After stirring at 0° C. for 1 hour, the reaction mixture waswarmed to room temperature and was stirred for 16 hours. The volatileswere evaporated and the residue was dissolved in ethyl acetate andwashed successively with 1N hydrochloric acid, water, 50% saturatedsodium bicarbonate, and brine. The organic layer was dried (sodiumsulfate), filtered, and concentrated and the residue was flashchromatographed (Merck silica gel ) eluting with 1:1 hexane/ethylacetate to give 135 mg. of title product as a yellow oil. TLC (2:1hexane:ethyl acetate) R_(f) =0.41.

c) 3S- 3α(R*),7α!!-Hexahydro-3-(2-mercapto-1-oxo-3-phenylpropyl)amino!-7-methyl-2-oxo-1H-azepine-1-aceticacid

A solution of the product from part (b) (130 mg., 0.32 mmol.) inmethanol (4 ml., deoxygenated via argon bubbling) was cooled to 0° C.and treated with 1N sodium hydroxide (3 ml., deoxygenated via argonbubbling). After being stirred under argon at 0° C. for 45 minutes, theresulting mixture was warmed to room temperature and stirred anadditional hour. The mixture was acidified with 10% potassium bisulfateand extracted with ethyl acetate. The organic layer was washedsuccessively with water and brine, dried (sodium sulfate), filtered andconcentrated to give a yellow oil. This residue was flashchromatographed (Merck silica gel) eluting with ethyl acetate and 1%acetic acid in 1:2 hexane/ethyl acetate. The fractions containing cleandesired product were combined, stripped, azeotroped with ethyl acetate,and washed with water to remove any acetic acid. The organic layer wasdried (sodium sulfate), filtered and concentrated. The residue was takenup in ethyl acetate and triturated with hexane. The solvent was removedand the residue was slurried in hexane, stripped, and dried in vacuo togive 103 mg. of title product as a white powdery foam; α!_(D) =+16.8°(c=0.28, methanol). TLC (1% acetic acid in 2:1 ethyl acetate/hexane)R_(f) =0.38.

Anal. calc'd. for C₁₈ H₂₄ N₂ O₄ S.0.31 H₂ O: C, 58.44; H, 6.70; N, 7.57;S, 8.67; Found: C, 58.65; H, 6.75; N, 7.36; S, 8.37.

EXAMPLE 66 S-(R*,R*)!-Hexahydro-6-(2-mercapto-1-oxo-3-phenylpropyl)amino!-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid

a) (2S)-2-Phthalimido-6-hydroxyheptanoic acid, phenylmethyl ester

A -78° C. solution of oxalyl chloride (3.0 ml., 4.36 g., 34.4 mmol.) inmethylene chloride (100 ml.) was treated dropwise with a solution of drydimethylsulfoxide (4.8 ml., 5.28 g., 67.6 mmol.) in methylene chloride(2.0 ml.). After 10 minutes, a solution of(S)-2-phthalimido-6-hydroxyhexanoic acid, phenylmethyl ester prepared asdescribed in Example 63(a) 10.365 g., 28.2 mmol.!in methylene chloride(20 ml.) was added over a 7 minute period. After an additional 15minutes, dry triethylamine (17 ml.) was added and the mixture wasstirred at -78° C. for 5 minutes, then allowed to gradually warm to 0°C. The mixture was partitioned between ethyl ether and water. Theorganic layer was washed with 1N hydrochloric acid and brine, dried(sodium sulfate), filtered and stripped to give the desired aldehyde asan oil. TLC (6:4 ethyl acetate:hexanes) R_(f) =0.56.

The oil was re-dissolved in dry methylene chloride (170 ml.), cooled inan ice bath, and treated dropwise with trimethylaluminum (2.0M inhexanes, 20.0 ml.). After 20 minutes, additional trimethylaluminumsolution (5.0 ml.) was added and stirring continued for 10 minutes. Themixture was cautiously quenched by the addition of saturated ammoniumchloride and then partitioned between ethyl ether and water. The aqueouslayer was back-extracted with ethyl acetate and the pooled organiclayers were washed with brine, dried (sodium sulfate), filtered andstripped to give a near colorless oil. Flash chromatography (Mercksilica gel, 6/4-ethyl acetate/hexanes) afforded 9.836 g. of pure titleproduct as a colorless oil. TLC (6:4 ethyl acetate:hexanes) R_(f) =0.41.

b) (S)-2-Phthalimido-6-oxoheptanoic acid, phenylmethyl ester

A -78° C. solution of oxalyl chloride (1.52 ml., 2.21 g., 17.4 mmol.) inmethylene chloride (120 ml.) was treated dropwise with a solution of drydimethylsulfoxide (2.50 ml., 2.75 g., 35.2 mmol.) in methylene chloride(2.0 ml.). After 10 minutes, a solution of the product from part (a)(5.078 g., 13.3 mmol.) in methylene chloride (30 ml.) was added. Afteran additional 15 minutes, dry triethylamine (10 ml.) was added and themixture was stirred at -78° C. for 5 minutes, then allowed to graduallywarm to 0° C. The mixture was partitioned between ethyl acetate and 1Nhydrochloric acid. The aqueous layer was back-extracted with ethylacetate and the pooled organic layers were washed with brine, dried(sodium sulfate), filtered and stripped. Flash chromatography (Mercksilica gel, 1/1-ethyl acetate/hexanes) afforded 4.892 g., of titleproduct as a colorless oil. TLC (1:1 ethyl acetate:hexanes) R_(f) =0.32;α!_(D) =-10.7° (c=0.9, chloroform).

c) (S)-2-Phthalimido-6-methyl-6-hydroxyheptanoic acid, phenylmethylester

Neat titanium tetrachloride (2.48 ml., 4.28 g., 22.5 mmol.) was addeddropwise to dry ethyl ether (150 ml.) at -78° C., resulting in a brightyellow suspension. The addition of methyl lithium (1.4M in ethyl ether,16.1 ml., 22.5 mmol.) over a 5 minute period afforded a dark-brownnon-homogeneous mixture. Gradual warming to -35° C. resulted in a deepbrown-purple near-homogeneous solution. The product from part (b) (5.682g., 15.00 mmol.) in ethyl ether (30 ml.) was added dropwise to the abovesolution, affording a gummy intractable reaction mixture. The reactionwas warmed to 0° C. and occasionally agitated with a spatula in order toeffect magnetic stirring. After 4 hours at 0° C., the mixture wasquenched with saturated ammonium chloride, diluted with water, andextracted with ethyl acetate. The organic layer was washed with waterand brine, dried (sodium sulfate), filtered and stripped. The residuewas flash chromatographed (Merck silica gel, 1/1-ethyl acetate/hexane)to afford 5.165 g., of title product as an oil; α!_(D) =-3.4° (c=0.7,chloroform). TLC (1:1 ethyl acetate:hexanes) R_(f) =0.25.

d) (S)-2-Phthalimido-6-methyl-6-azidoheitanoic acid, phenylmethyl ester

A solution of the product from part (c) (5.152 g., 13.0 mmol.) inmethylene chloride (120 ml.) was treated first with trimethylsilylazide(2.25 ml., 1.95 g., 17.0 mmol.) followed by boron trifluoride etherate(2.1 ml., 2.42 g., 17.1 mmol.). After stirring for 40 hours at roomtemperature, the mixture was quenched with water and extracted withethyl ether. The organic layer was washed with 50% saturated sodiumbicarbonate and brine, dried (sodium sulfate), filtered and stripped.The residue was flash chromatographed twice (Merck silica gel,25/75-ethyl acetate/hexanes) to give 4.165 g. of the desired product asa colorless oil; α!_(D) =-9.2° (c=0.6, chloroform). TLC (35:65 ethylacetate:hexanes) R_(f) =0.34.

e) (S)-Hexahydro-6-phthalimido-2,2-dimethyl-2Hazepin-7-one

A solution of the product from part (d) (5.550 g., 13.2 mmol.) indimethylformamide (90 ml.) was hydrogenated (balloon) over 10% palladiumon carbon (1.41 g.) at room temperature for 27 hours. The resultingthick mixture was evacuated, purged with nitrogen, and treated withdimethyl sulfide (100 μl., catalyst poison). The mixture wassubsequently treated with hydroxybenzotriazole (1.834 g.) followed byethyl-3-(dimethylamino)propyl carbodiimide (3.057 g., 16.0 mmol.) andthe viscous solution quickly became free flowing. After stirring for 16hours, the mixture was diluted with ethyl acetate and filtered throughCelite®. The filtrate was washed with 0.5N hydrochloric acid and waterand the pooled aqueous layers were back-extracted with ethyl acetate.The pooled organic layers were washed with 50% saturated sodiumbicarbonate and brine, then dried (sodium sulfate), filtered, andstripped to give a white solid. The solid was dissolved in hot ethylacetate/hexanes and cooled to give the product (2.652 g.) as fine whiteneedles. An additional 730 mg. of product was isolated from the motherliquor affording a total of 3.382 g. of the desired product; m.p.193°-194° C.; α!_(D) =+58.5° (c=1.2, chloroform). TLC (3:7 ethylacetate:methylene chloride) R_(f) =0.38.

Anal. calc'd. for C₁₆ H₁₈ N₂ O₃ : C, 67.12; H, 6.34; N, 9.78 Found: C,66.83; H, 6.31; N, 9.74.

f) (s)-Hexahydro-6-(1,1-dimethylethoxy)-carbonyl!amino!-2,2-dimethyl-2H-azepin-7-one

A solution of the product from part (e) (3.342 g., 11.7 mmol.) inmethylene chloride (10 ml.) and methanol (40 ml.) was treated withhydrazine monohydrate (775 μl., 800 mg., 16.0 mmol.). After stirring atroom temperature for 66 hours, the mixture was filtered and the solidwas washed with methanol. The filtrate was stripped, triturated withmethylene chloride and filtered again. Removal of the solvent affordedthe crude amine which was redissolved in methylene chloride (50 ml.) andsubsequently treated with di-tert-butyl dicarbonate (3.502 g., 16.0mmol.) and triethylamine (1.70 ml., 1.23 g., 12.2 mmol.). After 2.5hours at room temperature, the solvent was stripped and the residue wasflash chromatographed (Merck silica gel, 25/75-ethyl acetate/methylenechloride) to give 2.923 g. of title product as a white solid; m.p.118°-120° C.; α!_(D) =+38.4° (c=0.7, chloroform). TLC (25:75 ethylacetate:methylene chloride) R_(f) =0.33.

Anal. calc'd. for C₁₃ H₂₄ N₂ O₃ : C, 60.91; H, 9.44; N, 10.93; Found: C,61.27; H, 9.60; N, 10.86.

g) (S)-Hexahydro-6-(1,1-dimethylethoxy)carbonyl!-amino!2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid, ethyl ester

A room temperature solution of the product from part (f) (2.945 g., 11.5mmol.) in dry tetrahydrofuran (100 ml.) was treated with lithiumhexamethyldisilazide (1.0M in tetrahydrofuran, 17.0 ml.). After 4minutes, ethyl bromoacetate (1.90 ml., 2.86 g, 17.1 mmol.) was added tothe mixture. Additional lithium hexamethyl disilazane solution (17.0ml.) and ethyl bromoacetate (1.90 ml.) were added at both 20 and 40minutes after the first addition. One hour after the reaction wasinitiated, the mixture was quenched with saturated ammonium chloride andextracted with ethyl acetate. The ethyl acetate extract was washed withbrine, dried (sodium sulfate), filtered and stripped to give a brownliquid. Flash chromatography (Merck silica gel, 30 to 50% ethyl acetatein hexane) afforded 1.447 g. of title product as a pale yellow oil;α!_(D) =+10.6° (c=1.0, chloroform). TLC (1:1 ethyl acetate:hexanes)R_(f) =0.42.

h) S-(R*,R*)!-Hexahydro-6-2-(acetylthio)-1-oxo-3-phenylpropyl!amino!-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid, ethyl ester

A solution of the product from part (g) (764 mg., 2.23 mmol.) inp-dioxane (3.5 ml.) was treated with hydrochloric acid (4.0M inp-dioxane, 6.0 ml.). The mixture was stirred at room temperature for 2hours. The solvent was stripped and the residue was partitioned betweenhexane and water. The hexane layer was extracted again with 0.5Nhydrochloric acid and the pooled aqueous layers were made basic withsaturated sodium bicarbonate. The aqueous layer was extracted withmethylene chloride (4 times) and the pooled methylene chloride extractswere dried (sodium sulfate), filtered, and stripped to give the freeamine as a yellow oil.

A solution of (S)-(acetylthio)benzenepropanoic acid (obtained from thedicyclohexylamine salt as previously described, 603 mg., 2.69 mmol.) andthe above crude amine in methylene chloride (20 ml.) was treated withtriethylamine (357 μl., 259 mg., 2.56 mmol.) and the mixture was cooledto 0° C. Benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate (1.138 g., 25.7 mmol.) was then added as a solid.The solution was stirred at 0° C. for 1 hour and then at roomtemperature for 1 hour. The solvent was stripped and the residue waspartitioned between ethyl acetate and 0.5N hydrochloric acid. Theorganic layer was washed successively with water, 50% saturated sodiumbicarbonate and brine, then dried (sodium sulfate), filtered andstripped. The residue was flash chromatographed (Merck silica gel,1:1-ethyl acetate:hexanes) to give 804 mg. of the title product as anoil/foam. HPLC showed the product to be in 96.5% diastereomeric purity.TLC (1:1 ethyl acetate:hexanes) R_(f) =0.29.

i) S-(R*,R*)!-Hexahydro-6-(2-mercapto-1-oxo-3-phenylpropyl)amino!-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid

A room temperature solution of the product from part (h) (792 mg., 1.76mmol.) in methanol (6 ml., deoxygenated via argon bubbling) was treatedwith 1N sodium hydroxide (10 ml., deoxygenated via argon bubbling).After stirring under argon bubbling for 3 hours, the solution wasacidified with 10% hydrochloric acid and extracted with ethyl acetate.The ethyl acetate extract was washed with brine, then dried (sodiumsulfate), filtered and stripped to afford an oil. This material wasflash chromatographed (Merck silica gel, ethyl acetate followed by 1.5%acetic acid in ethyl acetate). The fractions containing the product werepooled, stripped, and azeotroped three times with ethyl acetate. Themixture was dissolved in a small amount of ethyl acetate and trituratedwith hexane to give a foam. The volatiles were stripped, the residue wasslurried in hexane for 1 hour, and the resulting precipitate wascollected by filtration and dried in vacuo to give 601 mg. of titleproduct as a hard white foam. NMR analysis shows the product to becomprised of a 95:5 mixture of diastereomers; α!_(D) =-18.4° (c=0.5,chloroform). TLC (2% acetic acid in ethyl acetate) R_(f) =0.36.

Anal. calc'd. for C₁₉ H₂₆ N₂ O₄ S: C. 60.30; H, 6.92; N, 7.40; S, 8.47;Found: C. 60.16; H, 7.06; N, 7.06; S, 8.10.

EXAMPLE 67 3S- 3α,6α(R*),9aβ!-Octahydro-6-(2-mercapto-1-oxo-3-phenylpropyl)amino!-5-oxo-1H-pyrrolo1,2-alazepine-3-carboxylic acid

a) (S)-2-Phthalimido-5-oxo-5-(phenylmethoxy)-pentanoic acid

To a solution of γ-benzyl-L-glutamate (17.49 g., 73.70 mmol.) in aqueous(180 ml.) sodium carbonate (7.81 g., 73.70 mmol.) and dioxane (120 ml.)was added N-carbethoxyphthalimide (16.50 g., 75.27 mmol., 1.02 eq.).After stirring at room temperature for 4.5 hours, The reaction mixturewas acidified with 6N hydrochloric acid (30 ml.) and extracted intoethyl acetate (2×400 ml.). The combined ethyl acetate extracts werewashed with 50% brine (200 ml.), and brine (200 ml.), dried over sodiumsulfate, filtered, concentrated and dried in vacuo to yield a crude oil(41.4 g.). To a solution of the crude residue in ethyl ether (100 ml.)was added dicyclohexylamine (14 ml.). After standing in the refrigeratorovernight, the ethyl ether was removed by rotary evaporation and theoily residue was crystallized from ethyl acetate/hexane. The resultingprecipitate was collected by filtration, washed with hexane and dried invacuo to yield 21.21 g. of the title product as the dicyclohexyl aminesalt. A suspension of this dicyclohexylamine salt in ethyl acetate (200ml.) was washed with 5% potassium bisulfate (3×50 ml.), brine (50 ml.)and dried over magnesium sulfate, filtered and concentrated to yield13.5 g. of the title product as a white foam. TLC: (3% acetic acid in9:1 ethyl acetate:heptane) R_(f) =0.30.

b) (S)-2-Phthalimido-5-oxo-5-(phenylmethoxy)-pentanoic acid, methylester

To a solution of the product from part (a) (13.22 g., 36.0 mmol.) andcesium carbonate (5.86 g., 18.0 mmol.) in dimethylformamide (100 ml.)was added iodomethane (8.1 ml., 129.6 mmol., 3.6 eq.). The yellowsolution was stirred for 2.5 hours, and was then partitioned betweenethyl acetate (300 ml.) and water (250 ml.). The ethyl acetate extractwas washed with 5% sodium bicarbonate (200 ml.) and brine, dried overmagnesium sulfate, filtered and concentrated to yield 13.68 g. a yellowoil. The residue was purified by chromatography on a 5×20 cm. silica gelcolumn eluting with 30% ethyl acetate/hexane. The desired fractions werecombined and concentrated to yield 10.0 g of the title product. TLC(1:1, ethyl acetate:hexane) R_(f) =0.45.

c) (S)-2-Phthalimido-4-(carboxy)butanoic acid, methyl ester

To a solution of the product from part (b) (10.0 g., 26.22 mmol.) inethyl acetate (115 ml.) was added 20% palladium hydroxide on carboncatalyst (1.90 g.) and the resulting suspension was stirred underhydrogen atmosphere (balloon) for 2.5 hours. The mixture was filteredthrough a millipore filter washing thoroughly with ethyl acetate,concentrated and dried in vacuo to yield 7.29 g. of crude title productas a white solid; m.p. 137°-138° C. TLC (10% methanol/methylenechloride) R_(f) =0.43.

d) (S)-2-Phthalimido-5-oxo-5-(ethylthio)pentanoic acid, methyl ester

To a solution of the product from part (c) (7.27 g., 24.95 mmol.) inmethylene chloride (125 ml.) at 0° C. under argon was added ethanethiol(4.81 ml., 64.92 mmol., 2.6 eq), 4-dimethylaminopyridine (609 mg., 4.99mmol., 0.2 eq.) and ethyl-3-(3-dimethylamino)propyl carbodiimide,hydrochloride salt (5.27 g., 27.47 mmol., 1.1 eq.). After stirring at 0°C. for 2 hours and at room temperature for 1 hour the reaction wasconcentrated, diluted with ethyl acetate (400 ml.) and washed with 5%potassium bisulfate (200 ml.), saturated sodium bicarbonate (200 ml.),and brine (200 ml.), dried over sodium sulfate, filtered, concentratedand dried in vacuo to yield 8.30 g. of title product as a crude oil. TLC(1:1, ethyl acetate:hexane) R_(f) =0.47.

e) (S)-2-Phthalimido-5-oxopentanoic acid, methyl ester

A suspension of the product from part (d) (8.30 g., 24.75 mmol.) and 10%palladium on carbon (1.24 g.) in acetonitrile (150 ml.) under argon wastreated dropwise with triethylsilane (7.91 ml., 49.5 mmol., 2 eq.).After stirring at room temperature for 45 minutes, the mixture wasfiltered through a millipore unit, concentrated and dried in vacuo. Thecrude residue was purified by chromatography on a 5×25 cm silica gelcolumn eluting with 25% ethyl acetate/hexane (41.) followed by 35% ethylacetate/hexane (21.). The desired fractions were combined to yield 5.60g. of title product. TLC (1:1, ethyl acetate:hexane) R_(f) =0.32.

f) (S)-2-Phthalimido-5,5-dimethoxypentanoic acid, methyl ester

A solution of the product from part (e) (5.60 g., 20.34 mmol.) inmethanol (60 ml.) and methylene chloride (40 ml.) was treated withtrimethylorthoformate (3.8 ml., 34.59 mmol., 1.7 eq.) andp-toluenesulfonic acid monohydrate (280 mg.). After stirring at roomtemperature for 1.5 hours the reaction was quenched with 2 ml. ofsaturated sodium bicarbonate, concentrated, and partitioned betweenethyl acetate (400 ml.) and water (100 ml.). The ethyl acetate extractwas washed with saturated sodium bicarbonate (100 ml.), brine (100 ml.),dried over magnesium sulfate, filtered and concentrated to a crude oil.The crude residue was purified by chromatography on a 5×20 cm silica gelcolumn eluting with 30% ethyl aceatate/hexane (21.). The desiredfractions were combined, concentrated and dried in vacuo to yield 6.20g. of title product. TLC (1:1, ethyl acetate:hexane) R_(f) =0.40.

a) S-(R*,R*)!-2-(2-Phthalimido-1-oxo-4-pentenyl)amino!-5,5-dimethoxypentanoic acid,ethyl ester

A solution of the product from part (f) (5.315 g., 16.5 mmol.) inmethanol (90 ml.) was treated with hydrazine monohydrate (870 μl., 898mg., 17.9 mmol.). After stirring at room temperature for 6 days, thesolution was filtered and evaporated, triturated with methylenechloride, filtered and evaporated again to give the crude free amine asa near colorless oil.

A solution of (S)-2-phthalimido-4-pentenoic acid prepared as describedin Example 35(b), 4.451 g., 18.1 mmol.! in methylene chloride (120 ml.)was treated with triethylamine (2.40 ml., 1.74 g., 17.2 mmol.) followedby the above primary amine in methylene chloride (20 ml.). The solutionwas cooled to 0° C. and subsequently treated withbenzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate(7.663 g., 17.3 mmol.) as a solid. The solution was stirred at 0° C. for1 hour and then at room temperature for 2.5 hours. The solvent wasstripped and the residue was partitioned between ethyl acetate andwater. The organic layer was washed successively with 50% saturatedsodium bicarbonate and brine, then dried (sodium sulfate), filtered andstripped. The residue was flash chromatographed (Merck silica gel,6:4-ethyl acetate:hexanes followed by 8:2-ethyl acetate:hexanes) to givethe desired product as a solid. Recrystallization from ethyl ether/ethylacetate afforded 4.466 g. of the title product; m.p. 83.5°-85.5° C.;α!_(D) =+15.3° (c=0.6, chloroform). TLC (6:4 ethyl acetate:hexanes)R_(f) =0.28.

Anal. calc'd. for C₂₁ H₂₆ N₂ O₇ : C, 60.28; H, 6.26; N, 6.69; Found: C,60.04; H, 6.22; N, 6.75.

h) S-(R*,R*)!-1-(2-Phthalimido-1-oxo-4-pentenyl)-1H-pyrrole-2-carboxylicacid, methyl ester

A solution of the product from part (g) (3.801 g., 9.08 mmol.) andtrifluoroacetic acid (1.0 ml.) in 1,1,1-trichloroethane (100 ml.) washeated at 60° C. under argon for 18 hours and then at reflux for anadditional 24 hours. The cooled mixture was quenched with saturatedsodium bicarbonate and water then extracted with ethyl acetate/ethylether. The organic layer was washed with brine, dried (sodium sulfate),filtered and stripped. The residue was flash chromatographed (Mercksilica gel, 50-60% ethyl acetate:hexanes) to afford the desired productas a solid. Recrystallization from methylene chloride/ ethyl etherprovided 2.068 g. of analytically pure title product; m.p. 147°-148° C.;α!_(D) =-273.2° (c=0.4, chloroform). TLC (6:4 ethyl acetate:hexanes)R_(f) =0.43.

Anal. calc'd. for C₁₉ H₁₈ N₂ O₅ : C, 64.40; H, 5.12; N, 7.91; Found: C,64.13; H, 4.95; N, 7.62.

i) 3S-(3α,6α,9aβ)!-Octahydro-8-iodo-5-oxo-6-phthalimido-1H-pyrrolo1,2-a!azepine-3-carboxylic acid, methyl ester

A cold (0° C.) solution of the product from part (h) (1.004 g., 2.83mmol.) in methylene chloride (10 ml.) was added dropwise to a mixture oftrifluoromethanesulfonic acid (1.5 ml.) and trifluoromethanesulfonicanhydride (150 μl.) at 0° C. The colorless solution was allowed to warmto room temperature. After 2.75 hours, the now bright yellow solutionwas poured into ice water and extracted with ethyl acetate. The ethylacetate extract was washed with brine, dried (sodium sulfate), filteredand stripped. The crude residue was dissolved in methyl ethyl ketone (15ml.) and treated with sodium iodide (1.98 g.). After stirring at roomtemperature for 1.5 hours, the mixture was partitioned between ethylacetate and water which contained a small amount of sodium bisulfite.The organic layer was washed with brine, dried (sodium sulfate),filtered and stripped. The residue was flash chromatographed twice(Merck silica gel, 6:4 ethyl acetate:hexanes) to give 799 mg. of titleproduct as a white foam; TLC (6:4 ethyl acetate:hexanes) R_(f) =0.31. Inaddition, 232 mg.of 3S-(3α, 6α, 8α, 9aβ)!-Octahydro-8-chloro-5-oxo-6-phthalimido-1H-pyrrolo1,2-a!azepine-3-carboxylic acid, methyl ester was also obtained as awhite foam. TLC (6:4 ethyl acetate:hexanes) R_(f) =0.25.

j) 3S-(3α, 6α, 9aβ)!-Octahydro-5-oxo-6-phthalimido-1H-pyrrolo1,2-a!azepine-3-carboxylic acid. methyl ester

A solution of the 8-iodo product from part (i) (705 mg., 1.46 mmol.) andtris(trimethylsilyl)silane (860 μl., 693 mg., 2.8 mmol.) in dry toluene(11 ml.) was heated to 55° C. and treated every 30 minutes with acatalytic amount (2-3 mg.) of 2,2'-azobisisobutyronitrile. After 2hours, the solution was cooled to room temperature and concentrated. Theresidue was flash chromatographed (Merck silica gel, 6:4 ethylacetate:hexanes) to give 470 mg. of title product as a white foam;α!_(D) =-36.4° (c=0.5, chloroform). TLC (6:4 ethyl acetate:hexanes)R_(f) =0.27.

k) 3S- 3α, 6α(R*),9aβ!!-Octahydro-6-2-(acetylthio)-1-oxo-3-phenylpropyl!amino!-5-oxo-1H-pyrrolo1,2-a!azepine-3-carboxylic acid, methyl ester

The product from part (j) (448 mg., 1.26 mmol.) in methanol (7 ml.) wastreated with hydrazine monohydrate (73 μl., 75 mg., 1.51 mmol.) and thesolution was stirred at room temperature for 42 hours. The mixture wasfiltered and the solid was washed with methanol. The filtrate wasstripped, triturated with methylene chloride, filtered again andevaporated to afford the crude amine as a pale yellow oil (277 mg.).

A cold (0° C.) solution of (S)-(acetylthio)benzenepropanoic acid(obtained from the dicyclohexylamine salt as described previously, 339mg., 1.51 mmol.) and the above amine in methylene chloride (10 ml.) wascooled to 0° C., then treated with triethylamine (193 μl., 140 mg., 1.38mmol.) followed by benzotriazol-1-yloxy-tris (dimethylamino)-phosphoniumhexafluorophosphate (641 mg., 1.45 mmol.). The solution was stirred at0° C. for 50 minutes and then at room temperature for 2 hours. Thesolvent was stripped and the residue was partitioned between ethylacetate and 0.5N hydrochloric acid. The organic layer was washedsuccessively with water, 50% saturated sodium bicarbonate and brine,then dried (sodium sulfate), filtered and stripped. The residue wasflash chromatographed (Merck silica gel, 6:4 ethyl acetate:hexanes) togive 461 mg. of pure title product as an oil/foam. TLC (75:25 ethylacetate:hexanes) R_(f) =0.36.

1) 3S- 3α, 6α(R*),9aβ!!-Octahydro-6-(2-mercapto-1-oxo-3-phenylpropyl)amino!-5-oxo-1H-pyrrolo1,2-a!azepine-3-carboxylic acid

A room temperature solution of the product from part (k) (456 mg., 1.05mmol.) in methanol (8 ml., deoxygenated via argon bubbling) was treatedwith 1N sodium hydroxide (9 ml., deoxygenated via argon bubbling). Afterstirring for 2.5 hours, the mixture was acidified with 10% hydrochloricacid, diluted with water and extracted with ethyl acetate. The ethylacetate extract was washed with brine, then dried (sodium sulfate),filtered and stripped. The residue was flash chromatographed (Mercksilica gel, ethyl acetate followed by 1% acetic acid in ethyl acetate).The desired product fractions were stripped, azeotroped three times withethyl acetate, taken up in a small amount of ethyl acetate andtriturated with hexanes. The solids were collected by filtration, washedwith hexane and dried n vacuo to afford 351 mg. of title product as awhite amorphous powder; α!_(D) =-107.9° (c=0.6, chloroform). TLC (2%acetic acid in ethyl acetate) R_(f) =0.35.

Anal. calc'd. for C₁₉ H₂₄ N₂ O₄ S: C, 60.62; H, 6.43; N, 7.44; S, 8.52;Found: C, 60.49; H, 6.42; N, 7.21; S, 8.39.

EXAMPLE 68 (2S)-8-(2-Mercapto-1-oxo-3-phenylpropyl)amino!-7-oxo-6-azaspiro4,6!undecane-6-carboxylic acid

a) 1-(4-Chlorobutyl)cyclopentanecarboxylic acid

A solution of lithium diisopropylamide was prepared under nitrogen fromdiisopropylamine (31.0 ml., 220 mmol.) and n-butyl lithium (1.5M inhexane, 88.0 ml., 220 mmol.) in tetrahydrofuran (80 ml.), maintainingthe temperature between -3° C.-10° C. After stirring 15 minutes,cyclopentanecarboxylic acid (11.4 g., 100 mmol.) in tetrahydrofuran (10ml.) was added at 0° C.-3° C. over 25 minutes. After an additional 15minutes at 0° C., the bath was removed and the reaction stirred 15minutes more, causing the temperature to rise to 11° C. The milky whitesolution was cooled to -74° C. and 1-bromo-4-chlorobutane (23 ml., 200mmol.) in tetrahydrofuran was added quickly, the temperature rising to-66° C. After 16 hours, the reaction was allowed to warm to roomtemperature in situ. The reaction was quenched with methanol (10 ml.)and concentrated in vacuo. The residue was partitioned between water(200 ml.) and ethyl ether (200 ml.). The aqueous layer was acidified topH 1 with 12M hydrochloric acid and extracted with methylene chloride(3×150 ml.), dried (magnesium sulfate), filtered and evaporated to give20.0 g. of the title product as a yellow oil.

b) 1-(4-Chlorobutyl)cyclopentanecarboxylic acid, methyl ester

To a solution of the product from part (a) (19.8 g., 96.5 mmol.) inmethylene chloride (100 ml.) was added diazomethane (prepared fromN-methyl-N'-nitro-N-nitrosoquanidine (22.8 g., 155 mmol.) in 40%potassium hydroxide (85 ml.) and ethyl ether (100 ml.)! until a yellowcolor was maintained. When all of the starting material had beenconsumed (monitored by TLC), nitrogen was bubbled through the reactionfor approximately 20 minutes. The solution was dried (magnesium sulfate)and the reaction stirred an additional 10 minutes before being filteredand concentrated in vacuo. The crude product was adsorbed onto silicagel, then purified by flash chromatography, eluting with 2:3 methylenechloride/hexane to give 17.1 g. of title product as as a clear oil.

c) 1-(4-Iodobutyl)cyclopentanecarboxylic acid, methyl ester

To a solution of the product from part (b) (15.0 g., 68.6 mmol.) inacetone (343 ml.) was added sodium iodide (51.4 g., 343 mmol.). Thesolution was stirred in the dark under nitrogen at 60° C. for 64 hours.The reaction was cooled to room temperature, diluted with ether andwashed with a saturated solution of sodium bicarbonate. The aqueousphase was extracted with ether (5×200 ml.). The ether extracts werecombined, washed with brine, dried (magnesium sulfate), filtered andconcentrated in vacuo to a clear oil (20.0 g). Purification by flashchromatography, eluting with 7:15 methylene chloride/hexane, gave 18.2g. of title product as a clear oil.

d) spiro 4,6!undecan-6-one

t-Butyl lithium (1.7M in pentane, 20.0 ml., 34 mmol.) was slowly addedto ether (38 ml.) at -20° C. as the reaction was further cooled to -100°C. in a methanol/dry ice/liquid nitrogen bath. To this -100° C. solutionwas added the product from part (c) (5.0 g., 16.1 mmol.) in 2:1ether/pentane (3 ml.) over 35 minutes, maintaining the temperature below-97° C. The reaction was warmed to -50° C. over two hours then quenchedwith a saturated solution of ammonium chloride, extracted with ethylacetate (4×100 ml.), washed with brine, dried (magnesium sulfate),filtered and concentrated to give a clear oil (mixture of desiredproduct and the iodo starting material).

e) Spiro 4,6!undecan-6-oxime

A solution of the crude mixture from part(d) (4.4 g., 29 mmol.),hydroxylamine.hydrochloride (4.7 g., 67 mmol.) and sodium acetate (5.7g., 70 mmol.) in isopropanol (30 ml.) was heated to 85° C. for twohours. The reaction was partitioned between ethyl ether and water. Theether extract was washed with 1N hydrochloric acid, brine, dried (sodiumsulfate) and concentrated to a clear oil. Purification by flashchromatography, eluting with 7:3 methylene chloride/hexane, gave 1.76 g.of title product as a white solid, m. p. 62°-63° C.

f) 8,8-Dichloro-6-azaspiro 4,6!undecan-7-one

A cold slurry of phosphorus pentoxide (6.57 g., 31.6 mmol.) in methylenechloride (7 ml.) was treated with a solution of the product from part(e) (1.76 g., 10.5 mmol.) in methylene chloride (10 ml.) over a threeminute period. The mixture was warmed to room temperature and chlorinegas was bubbled through the solution at 0.5 and 1.5 hours after theaddition of the oxime. After a total of three hours, the mixture wasquenched with crushed ice and brought to pH 8 with saturated sodiumbicarbonate solution. The biphasic mixture was stirred vigorously for 19hours. The layers were separated, washed with saturated sodiumbicarbonate solution, brine, dried (sodium sulfate), filtered andconcentrated in vacuo. Purification by flash chromatography, elutingwith 2:98 ether/methylene chloride, gave 952 mg. of title product as awhite solid; m.p. 114°-120° C.

g) 8-Chloro-6-azaspiro 4,6!undecan-7-one

To a solution of the product from part (f) (1.85 g., 7.83 mmol.) inglacial acetic acid (34 ml.) was added 10% palladium on carbon (0.55g.). The reaction was stirred under hydrogen at atmospheric pressure.After two hours, the reaction was purged with nitrogen, filtered throughCelite® and washed with ether. The oily solid was purified by flashchromatography, eluting with 4:96 ethyl acetate/methylene chloride togive 1.35 g. of the title product as a white solid; m.p. 109°-111° C.

h) 8-Azido-6-azaspiro 4,6!undecan-7-one

The product from part (g) (1.20 g., 5.95 mmol.), sodium azide (2.32 g.,35.7 mmol.) and sodium iodide (50 mg.) were combined indimethylsulfoxide (22 ml.) and heated to 80° C. under nitrogen. After 16hours, the solution was diluted with water and extracted with ether(4×50 ml.). The ether extracts were combined, washed with brine, dried(sodium sulfate), filtered and concentrated to a white solid.Purification by flash chromatography, eluting with 3:7 ethylacetate/hexane, gave 1.13 g. of title product as a white solid; m.p.96°-99° C.

i) 8- (1,1-Dimethylethoxy)carbonyl!amino!-6-azaspiro 4,6!undecan-7-one

To a solution of the product from part (h) (873 mg., 4.21 mmol.) inmethanol (17.5 ml.) was added 10% palladium on carbon catalyst (188 mg.)and the reaction was rapidly stirred under hydrogen at atmosphericpressure. After 90 minutes, the reaction was purged with nitrogen,filtered through Celite®, washed with methylene chloride and thefiltrate was concentrated in vacuo. The resulting white solid wasdissolved in chloroform (15 ml.), treated with triethylamine (0.59 ml.,4.21 mmol.) and then a solution of di-tert-butyl dicarbonate (1.1 g.,5.1 mmol.) in chloroform (2.5 ml.). After two hours at room temperature,the reaction was concentrated in vacuo. Purification by flashchromatography, eluting with 4:6 ethyl acetate/methylene chloride, gavea white solid which was repurified by flash chromatography, elutingfirst with methylene chloride (500 ml.) followed by 4:6 ethylacetate/methylene chloride, to give 1.00 g. of title product as a whitesolid; m.p. 180°-181° C.

j) 8- (1,1-Dimethylethoxy)carbonyl!amino!-7-oxo-6-azaspiro4,6!undecane-6-acetic acid, ethyl ester

To a solution of the product from part (i) (0.97 g., 3.4 mmol.) intetrahydrofuran (27 ml.) at room temperature was added lithium bis(trimethylsilyl)amide (5.1 ml., 5.1 mmol., 1M in tetrahydrofuran)followed by ethyl bromoacetate (0.78 ml., 6.8 mmol.). After stirringtwenty minutes at room temperature, another portion of lithiumbis(trimethylsilyl) amide (5.1 ml.) and ethyl bromoacetate (0.39 ml.)were added. The reaction was stirred for thirty minutes at roomtemperature and then treated with a third portion of lithiumbis(trimethylsilyl) amide and ethyl bromoacetate. One hour after thethird addition was complete, the reaction was quenched with a saturatedsolution of ammonium chloride, diluted with water (50 ml.), andextracted with ethyl acetate (3×50 ml.). The organic extracts were dried(sodium sulfate), filtered and concentrated to an orange oil.Purification by flash chromatography, eluting first with 3:7 ethylacetate/hexane followed by 50% ethyl acetate/hexane, gave 508 mg. oftitle product as a colorless oil.

k) 8-Amino-7-oxo-6-azaspiro 4,6!undecane-6-acetic acid ethyl ester,hydrochloride

A solution of the product from part (j) (507 mg., 1.38 mmol.; previouslyevaporated three times from toluene) in dioxane (1.0 ml.) at 0° C. wastreated with hydrochloric acid (4.0M in dioxane, 4.15 ml.). The reactionwas stirred 10 minutes at 0° C. and then warmed to room temperature.After 2.75 hours, the reaction was concentrated in vacuo to give 455 mg.of the title product as a white gummy solid.

1) (2S) -8- 2-(Acetylthio)-1-oxo-3-phenylpropyl!-amino!-7-oxo-6-azaspiro4,6!undecane-6-acetic acid, ethyl ester

(S)-(Acetylthio)benzenepropanoic acid, dicyclohexylamine salt (280 mg.,0.69 mmol.) was suspended in ethyl acetate, washed (3×) with 5%potassium bisulfate, dried (magnesium sulfate), filtered and evaporatedtwice from hexanes. To this was added the product from part (k) (200mg., 0.66 mmol.) in methylene chloride (6.6 ml.) at 0° C. followed bytriethylamine (137 mg., 1.4 mmol.). The reaction was stirred for tenminutes at 0° C. Benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (305 mg., 0.69 mmol.) was then added as a solid. Thesolution was stirred at 0° C. for 1.75 hours and then at roomtemperature for 10 minutes. The reaction was concentrated in vacuo andthe residue partitioned between ethyl acetate (50 ml.) and 5% potassiumbisulfate. The organic layer was washed with brine, a saturated solutionof sodium bicarbonate and brine, dried (magnesium sulfate), filtered andconcentrated to a yellow oil. Purification by flash chromatographyeluting with 2:3 ethyl acetate/hexane gave 241 mg. of title product as aclear oil.

m) (2S)-8- (2-Mercapto-1-oxo-3-phenylpropyl)amino!-7-oxo-6-azaspiro4,6!undecane-6-acetic acid

A solution of the product from part (1) (232 mg., 0.43 mmol.) inmethanol (5 ml., deoxygenated via nitrogen bubbling) was cooled to 0° C.and treated with 1N sodium hydroxide (5 ml., deoxygenated via nitrogenbubbling). After stirring for one hour at 0° C. while purgingcontinuously with nitrogen, the reaction was warmed to room temperature.After a total of three hours, the reaction was acidified to pH 1 with 5%potassium bisulfate and extracted with ethyl acetate. The organic layerswere combined, washed with water (50 ml.), brine, dried (sodiumsulfate), filtered, concentrated in vacuo, and reevaporated from hexanesto give 204 mg. of title product as a white foam. HPLC indicates theproduct to be a 47:53 mixture of diastereomers. TLC (2:3 ethylacetate:hexanes) R_(f) =0.22.

Anal. calc'd. for C₂₁ H₂₈ N₂ O₄ S.1.0C₄ H₈ O₂.0.03 C₆ H₁₄ : C, 61.07; H,7.41; N, 5.66; S, 6.47; Found: C, 60.61; H, 7.45; N, 5.97; S, 6.69.

EXAMPLE 69 (2S)-7-(2-Mercapto-1-oxo-3-phenylpropyl)amino!-6-oxo-5-azaspiro3,6!decane-5-acetic acid

a) 1-(4-Pentenyl)cyclobutanecarboxylic acid, phenylmethyl ester

To a solution of lithium diisopropylamide prepared from 31.0 ml. (221mmol.) of diisopropyl amine and 87.0 ml. (218 mmol., 2.5M in hexanes) ofn-butyllithium at 0° C. was added a solution of 10.01 g. (100.0 mmol.)of cyclobutanecarboxylic acid in 10 ml. of tetrahydrofuran over 5minutes. The temperature was not allowed to rise above 11° C. during theaddition. The resulting yellow, turbid solution was stirred for 30minutes, whereupon 14.0 ml. (118 mmol.) of 5-bromo-1-pentene was addedover the course of 5 minutes. The temperature rose autogenously to 50°C. over 10 minutes and then slowly subsided. When the temperaturereturned to 20° C., the reaction was quenched with 4 ml. of methanol andthen 20 ml. of water. The solution was concentrated under reducedpressure below 30° C. To the oily residue was added 100 ml. of water andthe mixture was extracted twice with 100 ml. portions of ether. Theaqueous layer was then acidified with cold 50% sulfuric acid to pH 2 andthen extracted three times with methylene chloride . The methylenechloride extracts were combined, dried (magnesium sulfate) andevaporated to give 17.61 g. of 1-(4-pentenyl)cyclobutanecarboxylic acidas a yellow oil.

To a stirred solution of this oil in 75 ml. of dimethylformamide at roomtemperature under nitrogen was added 32.8 g. (100 mmol.) of cesiumcarbonate and then 12.6 ml. (105 mmol.) of benzyl bromide. After 3hours, the reaction mixture was diluted with 200 ml. of water andextracted three times with ether. The combined extracts were washed oncewith water and once with brine, dried (magnesium sulfate) and evaporatedonto 40 g. of silica gel. Purification by flash chromatography (10×30 cmcolumn, 1:2 methylene chloride:hexanes) provided 22.65 g. of titleproduct as a colorless oil.

b) 1-(5-Hydroxypentyl)cyclobutanecarboxylic acid, phenylmethyl ester

To a solution of 20.0 g. (77.4 mmol.) of the product from part (a) in 75ml. of tetrahydrofuran under nitrogen at 0°-5° C. was added a solutionof 170 ml. (85.0 ml., 0.5M in tetrahydrofuran) of 9-borabicyclononaneover 20 minutes. The reaction was then warmed to room temperature andstirred for 45 minutes. To this solution was added 26 ml. (78 mmol.) ofice-cold 3M sodium hydroxide and then 26 ml. of 30% hydrogen peroxidewas added at a rate to keep the temperature below 48° C. After anadditional 30 minutes, the reaction was quenched with 100 ml. ofsaturated sodium sulfite solution. The reaction mixture was extractedthree times with ether, the extracts were combined, dried (magnesiumsulfate) and evaporated. Purification by flash chromatography (10×30 cmcolumn, 7:93 ether:methylene chloride) gave 19.15 g. of title product asa colorless oil.

c) 1- (Phenylmethoxy)carbonyl!cyclobutanepentanoic acid, methyl ester

To a stirred solution of 6.8 ml. (78 mmol.) of oxalyl chloride in 180ml. of methylene at -72° C. under nitrogen was added 12.2 ml. (172mmol.) of dimethylsulfoxide in 40 ml. of methylene chloride dropwiseover 10 minutes. The temperature was not allowed to rise above -60° C.After an additional 5 minutes, a solution of 18.66 g. (67.5 mmol.) ofthe product from part (b) in 30 ml. of methylene chloride was added over5 minutes. The resulting cloudy solution was stirred 15 minutes and thentreated with 30.8 ml. (186 mmol.) of diisopropylethylamine. The clearyellow solution was warmed to room temperature and treated with 100 mlof water. The aqueous layer was extracted once with 100 ml. of methylenechloride and the combined organic extracts were evaporated to leave afoul-smelling yellow oil.

The oil was dissolved in 140 ml. of 9:1 methanol/water and treated with120 g (1.4 mol) of solid sodium bicarbonate. The thick slurry wasrapidly stirred at room temperature while 142 ml. (0.28 mol.) of 2Mbromine in 9:1 methanol/water was added over 15 minutes. After 3 hours,the reaction was quenched with 20 ml. of saturated sodium thiosulfatesolution and evaporated below 30° C. to remove methanol. The pastyresidue was partitioned between water and ether. The aqueous layer wasextracted twice with ether, the organic layers were combined, dried(magnesium sulfate) and evaporated. Purification by flash chromatography(10×30 cm column, 1:9 hexanes/methylene chloride) gave 16.35 g. of titleproduct as a faintly yellow oil.

d) 1-Carboxycyclobutanepentanoic acid, methyl ester

20% Palladium hydroxide on carbon catalyst (1.3 g.) was added to theproduct from part (c) (16.30 g., 53.5 mmol.) in 100 ml. ofnitrogen-purged 3:1 ethyl acetate/ethanol in a 500 ml. Parrhydrogenation vessel. The reaction vessel was agitated on a ParrHydrogenator for 6 hours (hydrogen uptake was 5.9 psi). The reaction waspurged with nitrogen and filtered through Celite®. Additionalhydrogenation with fresh catalyst (2.0 g. of palladium hydroxide oncarbon) for 14 hours resulted in a total hydrogen uptake of 48 psi. Thereaction was repurged with nitrogen, filtered through Celite® andevaporated. Re-evaporation from toluene gave 11.40 g. of title productas a colorless oil.

e) 1-Aminocyclobutanepentanoic acid, methyl ester

To the product from part (d) (11.35 g., 53.0 mmol.)in tetrahydrofuran (5ml.) at 0° C. under nitrogen was added 7.8 ml. (56 mmol.) oftriethylamine and then 5.2 ml. (54.3 mmol.) of ethyl chloroformate,dropwise, over 15 minutes. The temperature was not allowed to rise above6° C. The resulting thick slurry was stirred for 10 minutes and thentreated rapidly with a slurry of 7.34 g. (113 mmol.) of sodium azide in40 ml. of 1:1 acetone/water. The solution thus formed was stirred for 15minutes, diluted with 100 ml. of ice water and extracted twice with 125ml. portions of toluene. The organic extracts were combined, washed oncewith 5% potassium bisulfate, once with brine, dried (magnesium sulfate)and filtered.

The filtrate was set to reflux with the aid of a Dean-Stark trap: 175ml. of solvent was removed from the reaction. After 30 minutes, theresidue was cooled to room temperature. The solution was diluted withmethylene chloride (50 ml.) under nitrogen at room temperature andtreated with 8.2 ml. (78 mmol.) of benzyl alcohol and 0.4 ml. (4.5mmol.) of chlorotrimethylsilane. After 40 minutes, the reaction wasquenched with 5 ml. of saturated sodium bicarbonate solution,partitioned, dried (magnesium sulfate) and evaporated.

The resulting oil was dissolved in 100 ml. of nitrogen-purged methanol,treated with 1.7 g. of 20% palladium hydroxide on carbon catalyst andhydrogenated on a Parr Hydrogenator for 16 hours (total hydrogen uptakeof 33.8 psi.). The reaction mixture was purged with nitrogen andevaporated. The residue was diluted with ether and washed three timeswith 10% hydrochloric acid. The acidic extracts were combined and washedthree times with ether. The aqueous layer was made basic with potassiumhydroxide pellets to pH 8.5 and extracted twice with methylene chloride.The organic extracts were dried (sodium sulfate) and evaporated toprovide essentially pure title product as a colorless oil.

f) 5-Azaspiro 3,6!decan-6-one

To a stirred solution of of the product from part (e) (4.16 g., 22.5mmol.) in methylene chloride (50 ml.) under nitrogen at room temperaturewas added 20 ml. (40 mmol.) of 2M trimethylaluminum in heptane over 5minutes. The reaction was stirred for 15 hours and then quenched withsaturated ammonium chloride solution and extracted twice with methylenechloride. The extracts were combined, dried (magnesium sulfate) andevaporated. Recrystallization from ethyl acetate/hexane gave 3.32 g. oftitle product as a white solid.

g) 5-(2-Propenyl)-5-azaspiro 3,6!undecan-6-one

To a stirred solution of 3.26 g. (21.3 mmol.) of the product from part(f) in 25 ml. of dimethylsulfoxide under nitrogen at room temperaturewas added 2.86 g. (25.5 mmol.) of potassium t-butoxide. The slurry washeated to 50° C. for 1 hour and then 2.5 ml. (28.9 mmol.) of allylbromide was added. A white precipitate formed instantly. After 3 hours,an additional 2.86 g. of potassium t-butoxide was added. A brown slurryformed. After 30 minutes, an additional 2.5 ml. of allyl bromide wasadded and the color faded at once. After 16 hours, a third batch of 2.5ml. of allyl bromide was added and the reaction stirred for 2 hours. Thereaction was then cooled, quenched with 5% potassium bisulfate andextracted four times with 100 ml. of ether. The combined extracts werewashed once with water, once with brine, dried (magnesium sulfate) andevaporated. Purification by flash chromatography (5×25 cm column, 55:45ethyl acetate/hexanes) gave 2.80 g. of title product as a light yellowoil.,

h) 5-(2,2-Dimethoxyethyl)-5-azaspiro 3,6!undecan-6-one

To a solution of 2.75 g. (14.2 mmol.) of the product from part (g) in 50ml. of methylene chloride at -78° C. in a flask protected by a calciumchloride drying tube was bubbled 8% ozone in oxygen gas until a bluecolor persists in the reaction mixture (about 2 hours). The reaction wasbriefly purged with oxygen and then nitrogen for 30 minutes. To thissolution was added 10 ml. of dimethylsulfide and the cold bath wasremoved. Upon warming to room temperature, the reaction mixture wasevaporated and the oily residue was dissolved in 20 ml. of methylenechloride, 30 ml. of methanol and 5 ml. of trimethylorthoformate. To thisstirred solution under nitrogen at room temperature was added 75 mg.(0.4 mmol.) of p-toluenesulfonic acid hydrate. The reaction was stirred16 hours, 1 g. (12 mmol.) of solid sodium bicarbonate was added, andstirred an additional 30 minutes. The reaction was partitioned betweenethyl acetate and saturated sodium bicarbonate solution and extractedagain with ethyl acetate. The organic extracts were combined, washedonce with brine, dried (sodium sulfate) and evaporated. Purification byflash chromatography (5×25 cm column, 4:1 ethyl acetate/hexane) provided1.60 g. of title product as a colorless oil.

i) 7-Bromo-5-(2,2-dimethoxyethyl)-5-azaspiro- 3,6!undecan-6-one

To a solution of lithium diisopropylamide prepared from 0.56 ml. (4.0mmol.) of diisopropyl amine and 1.60 ml. (4.0 mmol., 2.5M in hexanes) ofn-butyl lithium at 0° C. was added a solution of 908 mg. (3.76 mmol.) ofthe product from part (h) in 4 ml. of tetrahydrofuran over 2 minutes.The reaction was warmed to -45° C. and stirred 45 minutes. To this paleyellow solution was added a solution of 1.37 g. (4.11 mmol.) of carbontetrabromide in 5 ml. of tetrahydrofuran over 15 minutes. The resultingdeep red-brown solution was stirred for 20 minutes, quenched cold withsaturated ammonium chloride solution and extracted twice with ethylacetate. The extracts were combined, washed once with brine, dried(sodium sulfate) and evaporated. Purification by flash chromatography(5×15 cm column, 3:7 ethyl acetate/hexane) provided 1.012 g. of titleproduct as white solid, m.p. 62°-64° C.

j) 7-Azido-6-oxo-5-azaspiro 3,6!decane-5-acetaldehyde

To a stirred solution of 810 mg. (2.53 mmol.) of the product from part(i) in 10 ml. of dimethylsulfoxide at room temperature under nitrogenwas added 1.6 g. (25 mmol.) of sodium azide. The reaction was heated to45°-55° C. and stirred 16 hours. After cooling to room temperature, theslurry was diluted with 25 ml. of water and extracted three times withether. The extracts were combined, washed once with water, once withbrine, dried (sodium sulfate) and evaporated to give 680 mg. of theazidoacetal as a brown oil.

To a solution of this azide in 5 ml. of methylene chloride at roomtemperature under nitrogen was added 2.5 ml. of water and then 2.5 ml.of trifluoroacetic acid. After 1 hour, the reaction mixture was pouredinto a slurry of 8 g. of sodium bicarbonate in 15 ml. of water(considerable foaming). The mixture was extracted twice with ethylacetate. The extracts were combined, washed once with saturated sodiumbicarbonate, once with brine, dried (magnesium sulfate) and evaporatedto give 466 mg. of title product as an orange oil.

k) 7-Azido-6-oxo-5-azaspiro 3,6!decane-5-acetic acid, methyl ester

To a stirred slurry of 465 mg. (1.97 mmol.) of the product from part (j)and 8 g. (95 mmol.) of sodium bicarbonate in 8 ml. of 9:1 methanol/waterat room temperature was added 8 ml. (16 mmol.) of 2M bromine in 9:1methanol/water. The reaction was stirred for 4 hours, then quenched withsaturated sodium thiosulfate solution and extracted twice with ethylacetate. The extracts were combined, washed once with brine, dried(magnesium sulfate) and evaporated. Purification by flash chromatography(2.5×20 cm column, 1:2 ethyl acetate/hexanes) gave 275 mg. of titleproduct as a colorless oil.

l) 7-Amino-6-oxo-5-azaspiro 3,6!decane-5-acetic acid, methyl ester

To a stirred solution of 250 mg. (0.94 mmol.) of the product from part(k) in 15 ml. of dry, nitrogen-purged methanol at room temperature wasadded 320 mg. of 10% palladium on carbon. A hydrogen-filled balloon wasattached to the reaction flask and the reaction mixture was stirredrapidly. After 2 hours, the reaction was purged with nitrogen, filteredthrough Celite® and evaporated to give 215 mg. of title product as acolorless oil.

m) (2S)-7- 2-(Acetylthio)-1-oxo-3-phenylpropyl!-amino!-6-oxo-5-azaspiro3,6!decane-5-acetic acid, methyl ester

A stirred suspension of (S)-(acetylthio)-benzenepropanoic acid preparedfrom the dicyclohexylamine salt as described previously (324 mg., 0.80mmol.) in ethyl acetate (15 ml.) was washed twice with 5% potassiumbisulfate (5 ml.). The organic extract was dried (magnesium sulfate),filtered and evaporated twice from methylene chloride. The resulting oilwas dissolved methylene chloride (15 ml.) and stirred under argon at -5°C. To this solution was added a solution of the product from part (1)(174 mg., 0.724 mmol.) in methylene chloride (4 ml.), then triethylamine(100 μl., 0.74 mmol.) and finally benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (325 mg., 0.733 mmol.).After 1 hour, the reaction was warmed to room temperature and stirred 3hours. The resulting colorless solution was evaporated at less than 30°C. and the oily residue redissolved in ethyl acetate. The solution waswashed once with 1M hydrochloric acid, once with water and once withbrine. The organic layer was dried (magnesium sulfate), filtered andevaporated. Purification by flash chromatography (2.5×20 cm column,eluting with 47:53 ethyl acetate/hexanes) provided 240 mg. of titleproduct as a white foam.

n) (2S)-7- (2-Mercapto-1-oxo-3-phenylpropyl)amino!-6-oxo-5-azaspiro3,6!decane-5-acetic acid

A solution of the product from part (m) (145 mg., 0.32 mmol.) in 3 ml.of methanol was purged with nitrogen for 10 minutes and cooled to 0° C.To this solution was added dropwise 3 ml. of nitrogen-purged 1M sodiumhydroxide. Nitrogen was slowly bubbled through the solution during thereaction. After 30 minutes, the reaction was warmed to room temperatureand stirred 3 hours. The reaction was acidified with 1 ml. of 6Mhydrochloric acid, extracted twice with ethyl acetate and the extractscombined, dried (magnesium sulfate) and evaporated. Purification byflash chromatography (2.5×15 cm column, 1:79:20 acetic acid/ethylacetate/hexanes) gave, after re-evaporation from toluene, 118 mg. oftitle product as a white foam. TLC (79:20:1, ethyl acetate:hexane:aceticacid) R_(f) =0.20.

Anal. calc'd. for C₂₀ H₂₅ N₂ O₄ S.0.33 C₇ H₈.0.04 C₆ H₁₄ : C, 63.83; H,6.94; N, 6.60; S, 7.56; Found: C, 63.72; H, 6.90; N, 6.29; S, 7.42.

EXAMPLE 70 S-(R*,R*)!-Hexahydro-6-(2-mercapto-1-oxo-3-phenylpropyl)amino!-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid

The product of Example 66 was also prepared as follows:

a) (S)-Hexahydro-6-(triphenylmethyl)amino!-2,2-dimethyl-2H-azepine-7-one

Hydrazine monohydrate (4.59 ml., 94.6 mmol.) was added to a solution of(S)-hexahydro-6-phthalimido-2,2-dimethyl-2H-azepine-7-one preparred asdescribed in Example 66(e), 19.98 g., 68.76 mmol.! in methanol (250 ml.)at room temperature under argon. The resulting mixture was stirred for72 hours then filtered to remove the white precipitate. The volatileswere evaporated and the residue was dissolved in methylene chloride (560ml.) and filtered to remove additional precipitate. To this filtrate wasadded triethylamine (13.3 ml., 96.21 mmol.) followed bytriphenylchloromethane (20.65 g., 74.07 mmol.) and the resulting mixturewas stirred for 1.5 hours. Additional triphenylchloromethane (958 mg.,3.44 mmol.) was added and the solvent was removed. The residue waspartitioned between ethyl acetate and water. The organic layer waswashed with brine, dried, filtered and concentrated to give a paleyellow foam. Following a crystallization from ethyl acetate and hexanes,7.47 g. of title product was obtained as off-white crystals. The motherliquor was concentrated and crystallized from ethyl acetate and pentaneto give a second crop (8.02 g.) of title product. The mother liquor wasconcentrated and the residue was flash chromatographed (E Merck silicagel) eluting with 4.5:5.5 ethyl acetate/hexanes to give 6.0 g of titlecompound as a white foam. The combined yield of title product was 21.49g.; m.p. 139°-140° C.; α!_(D) =+43.4° (c=0.37, methylene chloride). TLC(2:3 hexane:ethyl acetate) R_(f) =0.63.

b) (S)-Hexahydro-6-(triphenylmethyl)amino!-2,2-dimethyl-7-oxo-1H-azepine-1-acetic acid,ethyl ester

Lithium bis(trimethylsilyl)amide (1.0M in tetrahydrofuran; 212.8 ml.,212.8 mmol.) and ethyl bromoacetate (23.6 ml., 212.8 mmol., in 190 ml.tetrahydrofuran) were simultaneously added to a solution of the productfrom part (a) (21.0 g., 53.19 mmol.) in tetrahydrofuran (210 ml.) atroom temperature under argon over 1 hour. Additional lithiumbis(trimethylsilyl)amide (1.0M in tetrahydrofuran; 53.2 ml., 53.2 mmol.)and ethyl bromoacetate (59.0 ml., 53.2 mmol., in 47.3 ml.tetrahydrofuran) were simultaneously added over 40 minutes then thereaction mixture was quenched with saturated aqueous ammonium chlorideand extracted with ethyl acetate. The organic layer was washed withsaturated aqueous sodium bicarbonate and brine, dried (sodium sulfate),filtered and concentrated to give a yellow oil. The residue was flashchromatographed twice (E Merck silica gel) eluting with 1:1hexanes/ethyl acetate and 3:1 hexanes/ethyl acetate to give 25.93 g. ofimpure title product. TLC (3:2 hexane:ethyl acetate) R_(f) =0.55.

c) S-(R*,R*)!-Hexahydro-6-2-(acetylthio)-1-oxo-3-phenylpropyl!amino!-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid, ethyl ester

A solution of the product from part (b) (25.92 g.) in methylene chloride(450 ml.) was treated with trifluoroacetic acid (14.82 ml., 192.4 mmol.)at room temperature under argon. After stirring for one hour, thevolatiles were evaporated and the residue was partitioned between ethylether and 1N hydrochloric acid. The organic layer was extracted with 1Nhydrochloric acid and water, the combined aqueous layers were cooled to0° C., and the pH was made basic with solid sodium bicarbonate.Following three extractions with methylene chloride, the combinedorganic layers were dried (sodium sulfate), filtered, and concentratedto give 7.0 g. of the pure amine as a yellow oil.

(S)-(Acetylthio)benzenepropanoic acid, dicyclohexylamine salt (7.55 g.,18.61 mmol.) was partitioned between ethyl acetate and 10% potassiumbisulfate. The organic layer was washed with 10% potassium bisulfate andbrine, dried (sodium sulfate), filtered, and concentrated to give(S)-(acetylthio)benzenepropanoic acid as an oil. This residue wasdissoved in methylene chloride (185 ml.) at room temperature underargon. Following the addition of the above amine (4.1 g., 16.92 mmol.),the mixture was cooled to 0° C. and triethylamine (2.59 ml.) was added.The resulting mixture was stirred for 5 minutes thenbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphatereagent (8.31 g., 18.79 mmol.) was added. After stirring at 0° C. for 1hour, the reaction mixture was warmed to room temperature and wasstirred for 16 hours. The volatiles were evaporated and the residue wasdissolved in ethyl acetate and washed successively with 0.5Nhydrochloric acid, water, saturated aqueous sodium bicarbonate, andbrine. The organic layer was dried (sodium sulfate), filtered, andconcentrated, and the residue was flash chromatographed (E Merck silicagel) eluting with 1:1 hexane/ethyl acetate to give 6.94 g. of titleproduct as a yellow foam. TLC(l:l hexane:ethyl acetate) R_(f) =0.36.

d) S-(R,R*)!-Hexahydro-6-(2-mercapto-1-oxo-3-phenylpropyl)amino!-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid

A solution of the product from part (c) (6.94 g., 15.47 mmol.) inmethanol (55 ml., deoxygenated via argon bubbling) was treated with 1Nsodium hydroxide (90.3 ml., deoxygenated via argon bubbling). Afterstirring under argon for 4 hours, the mixture was acidified with 10%hydrochloric acid and extracted with ethyl acetate. The organic layerwas washed successively with water and brine, dried (sodium sulfate),filtered and concentrated to give a yellow residue. The residue wasflash chromatographed (E Merck silica gel) eluting with ethyl acetateand 2% acetic acid in ethyl acetate. The fractions containing cleandesired product were combined, concentrated, azeotroped with ethylacetate and washed with water to remove any acetic acid to give 2.2 g.of title product as white heavy crystals. Impure fractions werecombined, then concentrated to a white solid, and finally trituratedwith ethyl acetate to obtain 2.3 g. of title product for a total yieldof 4.5 g. of title product; m.p. 173°-176° C.; α!_(D) =-21.9° (c=0.29,chloroform). TLC (2% acetic acid in ethyl acetate) R_(f) =0.38.

Anal. calc'd. for C₁₉ H₂₆ N₂ O₄ S.0.2 C₄ H₈ O₂ : C, 60.04; H, 7.02; N,7.07; S, 8.09; Found C, 59.79; H, 6.97; N, 7.33; S, 8.35.

EXAMPLE 71

1000 tablets each containing the following ingredients:

    ______________________________________     S-(R*,R*)-2,3,4,5-Tetrtahydro-3-                         200       mg.     (2-mercapto-1-oxo-3-phenylpropyl)-    amino!-2-oxo-1H-benzazepine-2-acetic    acid    Cornstarch           100       mg.    Gelatin              20        mg.    Avicel (microcrystalline cellulose)                         50        mg.    Magnesium stearate   5         mg.                         375       mg.    ______________________________________

are prepared from sufficient bulk quantities by mixing the product ofExample 6 and cornstarch with an aqueous solution of the gelatin. Themixture is dried and ground to a fine powder. The Avicel and then themagnesium stearate are admixed with granulation. This mixture is thencompressed in a tablet press to form 1000 tablets each containing 200mg. of active ingredient.

In a similar manner, tablets containing 200 mg. of the product of any ofExamples 1 to 5 and 7 to 70 can be prepared.

Similar procedures can be employed to form tablets or capsulescontaining from 50 mg. to 500 mg. of active ingredient.

What is claimed is:
 1. A compound of the formula (I) ##STR69## andpharmaceutically acceptable salts thereof wherein: R₁ is hydrogen,##STR70## or R₁₈ --S--; R₂ and R₁₉ are independently selected from thegroup consisting of hydrogen, alkyl, cycloalkyl-(CH₂)_(m) --,substituted alkyl, aryl-(CH₂)_(m) --, substituted aryl-(CH₂)_(m) --, andheteroaryl-(CH₂)_(m) -- or R₂ and R₁₉ taken together with the carbonatom to which they are attached complete a cycloalkyl ring or abenzofused cycloalkyl ring;n is zero or one; m is zero or an integerfrom 1 to 6; R₃ is alkyl, substituted alkyl, cycloalkyl-(CH₂)_(m) --,aryl-(CH₂)_(m) --, substituted aryl-(CH₂)_(m) --, orheteroaryl-(CH₂)_(m) --; R₁₈ is alkyl, substituted alkyl,cycloalkyl-(CH₂)_(m) --, aryl-(CH₂)_(m) --, substituted aryl-(CH₂)_(m)--, heteroaryl-(CH₂)_(m) -- or --S--R₁₈ completes a symmetricaldisulfide wherein R₁₈ is of the formula (II) ##STR71## X₁ is of theformula (VI) ##STR72## (VII) ##STR73## R₆ and R₁₀ are independentlyselected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, cycloalkyl-(CH₂)_(m) --,aryl-(CH₂)_(m) --, substituted aryl-(CH₂)_(m) --, andheteroaryl-(CH₂)_(m) --; R₇ and R₁₁ are independently selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, cycloalkyl --(CH₂)_(m) --, aryl-(CH₂)_(m) --,substituted aryl-(CH₂)_(m) --, and heteroaryl-(CH₂)_(m) -- or R₆ and R₇taken together with the carbon to which they are attached complete asaturated cycloalkyl ring of 3 to 7 carbons; b is zero or one; s iszero, one or two; Y₁ is --O--or ##STR74## Y₄ is --O--; R₁₂ is hydrogen,alkyl, substituted alkyl, aryl-(CH₂)_(m) --, substituted aryl-(CH₂)_(m)--, heteroaryl-(CH₂)_(m) --, ##STR75## R₁₄ is hydrogen, lower alkyl,cycloalkyl, or phenyl; R₁₅ is hydrogen, lower alkyl, lower alkoxy orphenyl; R₁₆ is lower alkyl or aryl-(CH₂)_(m) --; the term "alkyl" refersto straight and branched chain radicals having one to seven carbonatoms; the term "substituted alkyl" refers to such straight or branchedchain radicals of 1 to 7 carbons wherein one or more hydrogens have beenreplaced by a hydroxy, amino, halo, trifluoromethyl, cyano, --NH(loweralkyl), --N(lower alkyl)₂, lower alkoxy, lower alkylthio or carboxy; theterm "alkenyl" refers to straight or branched chain radicals of 3 to 7carbon atoms having one or two double bonds; the term "substitutedalkenyl" refers to such straight or branched radicals of 3 to 7 carbonshaving one or two double bonds wherein a hydrogen has been replaced by ahydroxy, amino, halo, trifluoromethyl, cyano, --NH(lower alkyl),--N(lower alkyl)₂, lower alkoxy, lower alkylthio, or carboxy; the term"cycloalkyl" refers to saturated rings of 3 to 7 carbon atoms; the term"aryl" refers to phenyl, 1-naphthyl, and 2-naphthyl; the term"substituted aryl" refers to phenyl, 1-naphthyl, and 2-naphthyl having asubstituent selected from lower alkyl, lower alkoxy, lower alkylthio,halo, hydroxy, trifluoromethyl, amino, --NH(lower alkyl), and --N(loweralkyl)₂, di- and tri-substituted phenyl, 1-naphthyl, or 2-naphthylwherein said substituents are selected from methyl, methoxy, methylthio,halo, hydroxy, and amino; the term "heteroaryl" refers to unsaturatedmonocyclic rings of 5 or 6 atoms containing one or two O and S atomsand/or one to four N atoms provided that the total number of heteroatoms is four or less and all other atoms in the ring are C and bicyclicrings wherein the five or six membered ring as defined above is fused toa phenyl or pyridyl ring, said heteroaryl ring is attached by way of anavailable carbon or nitrogen atom; and said monocyclic or bicyclic ringcan be substituted at an available carbon atom by lower alkyl of 1 to 4carbons, halo, hydroxy, benzyl, or cyclohexylmethyl, or can besubstituted at an available nitrogen atom by benzyloxymethyl, p-toluenesulfonyl, 2,4-dinitrophenyl, lower alkyl of 1 to 4 carbons, benzyl orbenzhydryl; the term "lower alkyl" refers to straight or branched chainradicals having one to four carbons; the term "substituted lower alkyl"refers to such straight or branched chain radicals having one to fourcarbons wherein one hydrogen has been replaced by a hydroxy, amino,halo, trifluoromethyl, cyano, --NH(lower alkyl), --N(lower alkyl)₂,lower alkoxy, lower alkylthio, or carboxy; the terms "lower alkoxy" and"lower alkylthio" refer to such lower alkyl groups as defined aboveattached to an oxygen or sulfur; and the term "halo" refers to chloro,bromo, fluoro, and iodo.
 2. A compound of claim 1 wherein:X₁ is of theformula ##STR76##
 3. A compound of claim 2 wherein:R₁ is hydrogen,##STR77## or R₁₈ --S--; R₃ is lower alkyl of 1 to 4 carbons or phenyl;R₁₈ is lower alkyl of 1 to 4 carbons; n is zero or one; R₂ is aryl-CH₂--, substituted aryl-CH₂ --, heteroaryl-CH₂ --, or straight or branchedchain alkyl of 1 to 7 carbons; and R₁₉ is hydrogen.
 4. A compound ofclaim 3 wherein:Y₁ is O or S; R₆ and R₇ are both hydrogen or R₆ is loweralkyl of 1 to 4 carbons and R₇ is hydrogen; R₁₀ and R₁₁ are bothhydrogen or one is hydrogen and the other is lower alkyl of 1 to 4carbons; b is zero; and R₁₂ is hydrogen or lower alkyl of 1 to 4carbons.
 5. A compound of claim 4 wherein:Y₁ is O.
 6. A compound ofclaim 5 whereinR₁ is hydrogen; n is zero; R₂ is benzyl,(2-thienyl)methyl, or straight or branched chain alkyl of 1 to 5carbons.
 7. The compound of claim 6, S-(R*,R*)!-3,4-dihydro-3-(2-mercapto-1-oxo-3-phenylpropyl)amino!-4-oxo-1,5-benzoxazepine-5(2H)-aceticacid.
 8. The compound of claim 6, 2S- 2α,3β(R*)!!-3,4-dihydro-3-(2-mercapto-1-oxo-3-phenylpropyl)-amino!-2-methyl-4-oxo-1,5-benzoxazepine-5(2H)-aceticacid.
 9. A compound of claim 4 wherein:Y₁ is S.
 10. A compound of claim9 whereinR₁ is benzyl, (2-thienyl)methyl, or straight or branched chainalkyl of 1 to 5 carbons.
 11. The compound of claim 10,R-(R*,S*)!-3,4-dihydro-3-(2-mercapto-1-oxo-3-phenylpropyl)amino!-4-oxo-1,5-benzothiazepine-5(2H)-aceticacid.
 12. A compound of claim 1 wherein:X₁ is of the formula (VII)##STR78##
 13. A compound of claim 12 wherein:Y₄ is O; R₁ is hydrogen,##STR79## or R₁₈ --S--; R₃ is lower alkyl of 1 to 4 carbons or phenyl;R₁₈ is lower alkyl of 1 to 4 carbons; n is zero or one; R₂ is aryl-CH₂--, substituted aryl-CH₂ --, heteroaryl-CH₂ --, or straight or branchedchain alkyl of 1 to 7 carbons; and R₁₉ is hydrogen.
 14. A compound ofthe formula: ##STR80## including a pharmaceutically acceptable saltthereof wherein: R₁ is hydrogen or ##STR81## R₂ is hydrogen, alkyl,cycloalkyl-(CH₂)_(m) --, substituted alkyl, aryl-(CH₂)_(m) --,substituted aryl-(CH₂)_(m) --, or heteroaryl-(CH₂)_(p) --;n is zero orone; m is zero or an integer from 1 to 6; p is an integer from 1 to 6;R₃ is alkyl, substituted alkyl, cycloalkyl-(CH₂)_(m) --, aryl-(CH₂)_(m)--, substituted aryl-(CH₂)_(m) --, or heteroaryl-(CH₂)_(m) --; X₁ is##STR82## R₁₀ is hydrogen, alkyl, substituted alkyl, aryl-(CH₂)_(p) --,or substituted aryl-(CH₂)_(p) --; R₁₂ is hydrogen, alkyl, substitutedalkyl, aryl-(CH₂)_(m) --, or substituted aryl-(CH₂)_(m) --; Y₁ is O, S;b is zero or one; the term "alkyl" refers to straight and branched chainradicals having one to seven carbon atoms; the term "cycloalkyl" refersto saturated rings of 4 to 7 carbon atoms; the term "substituted alkyl"refers to such straight and branched chain radicals having to 1 to 7carbon atoms wherein one or more hydrogens have been replaced by ahydroxy, amino, halo, trifluoromethyl, --NH(lower alkyl of 1 to 4carbons), --N(lower alkyl of 1 to 4 carbons)₂, lower alkoxy of 1 to 4carbons, or lower alkylthio of 1 to 4 carbons; the term "aryl" refers tophenyl, 1-naphthyl, and 2-naphthyl; the term "substituted aryl" refersto phenyl, 1-naphthyl and 2-naphthyl having a substituent selected fromlower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, loweralkylthio of 1 to 4 carbons, halo, hydroxy, trifluoromethyl, amino,--NH(lower alkyl of 1 to 4 carbons), and --N(lower alkyl of 1 to 4carbons)₂, and di- and tri-substituted phenyl, 1-naphthyl, and2-naphthyl wherein said substituents are selected from methyl, methoxy,methylthio, halo, hydroxy, and amino; and the term "heteroaryl" refersto unsaturated monocyclic rings of 5 of 6 atoms containing one or two Oand S atoms and/or one to four N atoms provided that the total number ofhetero atoms is four or less and all other atoms in the ring are C andbicyclic rings wherein the five or six membered ring as defined above isfused to a phenyl or pyridyl ring, said heteroaryl ring is attached byway of an available carbon or nitrogen atom; and said monocyclic orbicyclic ring can be substituted at an available carbon atom by a loweralkyl of 1 to 4 carbons, halo, hydroxy, benzyl, or cyclohexylmethyl, orcan be substituted at an available nitrogen atom by benzyloxymethyl,p-toluene sulfonyl, 2,4-dinitrophenyl, lower alkyl of 1 to 4 carbons,benzyl, or benzhydryl.
 15. A compound of the formula (I) ##STR83## andpharmaceutically acceptable salts thereof wherein: R₁ is hydrogen,##STR84## or R₁₈ --S--; R₂ and R₁₉ are independently selected from thegroup consisting of hydrogen, alkyl, cycloalkyl-(CH₂)_(m) --,substituted alkyl, aryl-(CH₂)_(m) --, substituted aryl-(CH₂)_(m) --, andheteroaryl-(CH₂)_(m) --;n is zero or one provided that n must be zerowhen R₂ and R₁₉ are both other than hydrogen; m is zero or an integerfrom 1 to 6; R₃ is alkyl, substituted alkyl, cycloalkyl-(CH₂)_(m) --,aryl-(CH₂)_(m) --, substituted aryl-(CH₂)_(m) --, orheteroaryl-(CH₂)_(m) --; R₁₈ is alkyl, substituted alkyl,cycloalkyl-(CH₂)_(m) --, aryl-(CH₂)_(m) --, substituted aryl-(CH₂)_(m)--, heteroaryl-(CH₂)_(m) -- or --S--R₁₈ completes a symmetricaldisulfide wherein R₁₈ is of the formula (II) ##STR85## X₁ is of theformula (VI) ##STR86## (VII) ##STR87## R₆ and R₁₀ are independentlyselected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, cycloalkyl-(CH₂)_(m) --,aryl-(CH₂)_(m) --, substituted aryl-(CH₂)_(m) --, andheteroaryl-(CH₂)_(m) --; R₇ and R₁₁ are independently selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, cycloalkyl-(CH₂)_(m) --, aryl-(CH₂)_(m),substituted aryl-(CH₂)_(m) --, and heteroaryl-(CH₂)_(m) -- or R₆ and R₇taken together with the carbon to which they are attached complete asaturated cycloalkyl ring of 3 to 7 carbons; b is zero or one; s iszero, one or two; Y₁ is --O-- ##STR88## Y₄ is --O--; R₁₂ is hydrogen,alkyl, substituted alkyl, aryl-(CH₂)_(m) --, substituted aryl-(CH₂)_(m)--, heteroaryl-(CH₂)_(m) --, ##STR89## R₁₄ is hydrogen, lower alkyl,cycloalkyl, or phenyl; R₁₅ is hydrogen, lower alkyl, lower alkoxy orphenyl; R₁₆ is lower alkyl or aryl-(CH₂)_(m) --; the term "alkyl" refersto straight and branched chain radicals having one to seven carbonatoms; the term "substituted alkyl" refers to such straight or branchedchain radicals of 1 to 7 carbons wherein one or more hydrogens have beenreplaced by a hydroxy, amino, halo, trifluoromethyl, cyano, --NH(loweralkyl), --N(lower alkyl)₂, lower alkoxy, lower alkylthio or carboxy; theterm "alkenyl" refers to straight or branched chain radicals of 3 to 7carbon atoms having one or two double bonds; the term "substitutedalkenyl", refers to such straight or branched radicals of 3 to 7 carbonshaving one or two double bonds wherein a hydrogen has been replaced by ahydroxy, amino, halo, trifluoromethyl, cyano, --NH(lower alkyl),--N(lower alkyl)₂, lower alkoxy, lower alkylthio, or carboxy; the term"cycloalkyl" refers to saturated rings of 3 to 7 carbon atoms; the term"aryl" refers to phenyl, 1-naphthyl, and 2-naphthyl; the term"substituted aryl" refers to phenyl, 1-naphthyl, and 2-naphthyl having asubstituent selected from lower alkyl, lower alkoxy, lower alkylthio,halo, hydroxy, trifluoromethyl, amino, --NH(lower alkyl), and --N(loweralkyl)₂, di- and tri-substituted phenyl, 1-naphthyl, or 2-naphthylwherein said substituents are selected from methyl, methoxy, methylthio,halo, hydroxy, and amino; the term "heteroaryl" refers to unsaturatedmonocyclic rings of 5 or 6 atoms containing one or two O and S atomsand/or one to four N atoms provided that the total number of heteroatoms is four or less and all other atoms in the ring are C and bicyclicrings wherein the five or six membered ring as defined above is fused toa phenyl or pyridyl ring, said heteroaryl ring is attached by way of anavailable carbon or nitrogen atom; and said monocyclic or bicyclic ringcan be substituted at an available carbon atom by lower alkyl of 1 to 4carbons, halo, hydroxy, benzyl, or cyclohexylmethyl, or can besubstituted at an available nitrogen atom by benzyloxymethyl, p-toluenesulfonyl, 2,4-dinitrophenyl, lower alkyl of 1 to 4 carbons, benzyl orbenzhydryl; the term "lower alkyl" refers to straight or branched chainradicals having one to four carbons; the term "substituted lower alkyl"refers to such straight or branched chain radicals having one to fourcarbons wherein one hydrogen has been replaced by a hydroxy, amino,halo, trifluoromethyl, cyano, --NH(lower alkyl), --N(lower alkyl)₂,lower alkoxy, lower alkylthio, or carboxy; the terms "lower alkoxy" and"lower alkylthio" refer to such lower alkyl groups as defined aboveattached to an oxygen or sulfur; and the term "halo" refers to chloro,bromo, fluoro, and iodo.